CN1098843C

CN1098843C - Isoxazoles

Info

Publication number: CN1098843C
Application number: CN95195758A
Authority: CN
Inventors: 小岛孝一; 酒井纯一; 相泽有一; 佐復直纯; 狐塚政雄; 吉见建二; 金子勳; 小山和男
Original assignee: Sankyo Co Ltd
Current assignee: Sankyo Co Ltd
Priority date: 1994-08-30
Filing date: 1995-08-29
Publication date: 2003-01-15
Anticipated expiration: 2015-08-29
Also published as: US6096771A; FI970864A; AU688102B2; WO1996006837A1; NO308741B1; HU221138B1; AU3266095A; DE69532039T2; EP0779281A1; CZ290961B6; CZ59897A3; ES2208690T3; NO970892L; EP0779281B1; NO970892D0; FI970864A0; KR970705549A; US5965591A; CA2198457A1; DK0779281T3

Abstract

An isoxazole derivative represented by general formula (I), having an excellent monoamine oxidase inhibitory activity, and being useful as a remedy or preventive for nervous diseases such as Parkinson's diseases, wherein R<1> represents hydrogen, halogen, alkyl, alkoxy, hydroxy, alkylthio, amino, alkanoyl, alkanoylamino, alkanoyloxy, alkoxycarbonyl, carboxy, (alkylthio)-thiocarbonyl, carbamoyl, nitro or cyano; R<2> represents amino; m represents an integer of 1 to 3; n represents an integer of 1 to 6; ring A represents benzene, naphthalene or aromatic heterocycle; and X represents oxygen or sulfur.

Description

Isoxazole derivatives

[technical field]

The present invention relates to include Parkinson's, depression and alzheimer's disease (particularly Parkinson's) with Type B and A MAO-B Bs inhibitory activity (particularly with significant monoamine oxidase B inhibitory action) and to neuropathy there are treatment or prevention to act on isoxazole derivativeses.The invention further relates to the MAOI containing isoxazole derivatives active component.

[background technology]

Parkinson's are a kind of chronic progressive diseases, and motion can be caused, myotonia and to tremble, and dopaminergic neuron in black substance as a result can be made to degenerate.It has been found that Parkinson's are due to caused by the reduction of dopamine brain concentration, dopamine is a kind of neurotransmitter, and basal ganglion degeneration, vascular and inflammatory activity are particularly caused in caudate nucleus and shell core.In order to supplement in brain particularly corpus straitum reduction dopamine, the maximally effective treatment method and method being commonly used is to apply levodopa.But, due to serious side reaction so that levodopa progress treatment is used alone and there are many problems.Recently, carried out many by suppressing monoamine oxidase B (a kind of dopamine catabolic enzyme) and preventing dopamine decomposition from treating the experiment of Parkinson's and developed a kind of MAOI-deprenyl.

Now, benzisoxazole derivatives such as compound A and B is disclosed in the clear 47-6302 of Japan Patent, they are typically applied to nervous system and with Cardiovascular, can be used as local anaesthetics, antihistaminic, anti-inflammatory agent, antasthenic and anti-spasmodics.

(compound A) (compound B)

In addition, being pointed out in Farmaco, Ed.Sci., 23,1081 (1968), ibid., 24,440 (1069), compound B has antiinflammatory action and with local (infiltration) anesthetic effect.But, then it is entirely ignorant of for the monoamine oxidase inhibitory activity of the compound A and B.

[content of the invention]

The present inventor concentrate on studies for a long time isoxazole compounds synthesis and pharmacological activity, purpose is the notable therapeutic agent for finding Parkinson's, it was found that with specific structure isoxazole derivativeses there is high inhibition to act on (inhibitory action to monoamine oxidase B is especially strong) and include Parkinson's, depression and alzheimer's disease (particularly Parkinson's) to neuropathy to Type B and A MAO-B Bs has treatment or prevention effect, thus complete the present invention.

The invention provides with significant monoamine oxidase B inhibitory activity and A MAO-B B inhibitory activity isoxazole derivativeses, their synthetic method and the MAOI containing isoxazole derivatives active component.

Isoxazole derivatives of the present invention is general formula (I) compound,Wherein R¹Represent hydrogen atom；Halogen atom；C₁-C₆Alkyl；Halogen-or C₁-C₄The C of alkoxy-substituted₁-C₄Alkyl；C₁-C₆Alkoxy；Halo C₁-C₆Alkoxy；Hydroxyl；C₁-C₆Alkylthio group；Amino；Single C₁-C₆Alkyl amino；Two C₁-C₆Alkyl amino；C₁-C₆Alkanoyl；C₁-C₆Alkanoyl amido；C₁-C₆Alkanoyloxy；C₁-C₆Alkoxy carbonyl group；Carboxyl；(C₁-C₆Alkylthio group) thiocarbonyl；Carbamoyl；Single C₁-C₆Alkyl-carbamoyl；Two C₁-C₆Alkyl-carbamoyl；Nitro or cyano group, R²Represent amino group, m represents 1-3 integer, n represents 1-6 integer, ring A represent the phenyl ring Yu isoxazole rings fusion of Yu isoxazole rings fusion naphthalene nucleus or the fusion of Yu isoxazole rings containing 1 or 25 or 6 yuan of heteroaromatic for being selected from oxygen, nitrogen and sulfur heteroatom, and X represents oxygen atom or sulphur atom, and condition is, when m is 2 or 3 integer, each substituent R¹It is identical or different.

In addition, MAOI active component of the present invention be general formula (II) isoxazole derivativeses,

Wherein R¹, m, n, ring A and X it is as defined above, and

R² _aRepresent amino；Single C₁-C₄Alkyl amino；Two C₁-C₄Alkyl amino；Or 5 or 6 circle heterocycles containing 1 nitrogen-atoms and arbitrarily containing another nitrogen-atoms or oxygen atom (condition is that relevant group is connected through the nitrogen-atoms).

In the logical formula (I) and (II), above-mentioned R¹Definition described in " halogen atom " can be fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine atom, and more preferably fluorine or chlorine atom.

Above-mentioned R¹Definition described in " C₁-C₆Alkyl group " is the straight or branched alkyl group of 1-6 carbon atom; they can be such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, 2- methyl butyls, neopentyl, 1- ethyl propyls, hexyl, 4- methyl amyls, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 3; 3- dimethylbutyls, 2; 2- dimethylbutyls, 1; 1- dimethylbutyls, 1; 2- dimethylbutyls, 1,3- dimethylbutyls, 2,3- dimethylbutyls or 2- ethyl-butyl groups, preferably C₁-C₄Alkyl, and more preferably methyl or ethyl.Particularly preferably methyl.

Above-mentioned R¹Definition described in " halogen-or C₁-C₄The C of alkoxy substitution₁-C₄Alkyl group " is by above-mentioned halogen or following C₁-C₄The above-mentioned C of alkoxy substitution₁-C₄Alkyl group；The halogen-substituted alkyl group can be such as methyl fluoride, difluoromethyl, trifluoromethyl, 2- fluoro ethyls, 2- chloroethyls, 2, 2, 2- trifluoroethyls, 3- fluoropropyls, 3- chloropropyls, 3- bromopropyls, 4- fluorine butyl or 4- chlorobutyl groups, and the alkoxy-substituted alkyl group can be methoxy, ethoxyl methyl, propoxy methyl, butoxymethyl, methoxy ethyl, ethoxyethyl group, Among, butoxyethyl group, propoxypropyl or butoxybutyl group, it is preferred that methyl fluoride, difluoromethyl, trifluoromethyl, 2- fluoro ethyls, 2- chloroethyls, 2, 2, 2- trifluoroethyls, methoxy or methoxyethyl groups, and more preferably methyl fluoride, difluoromethyl, trifluoromethyl, 2- fluoro ethyls, 2, 2, 2- trifluoroethyls, methoxy and methoxyethyl groups, and further preferably trifluoromethyl, 2, 2, 2- trifluoroethyls or methoxy.Particularly preferably trifluoromethyl.

Above-mentioned R¹Definition described in " C₁-C₆Alkoxy base " is above-mentioned " C₁-C₆The group of alkyl group " and oxygen atoms bond and they can be methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy, isoamoxy, 2- methylbutoxy groups, neopentyl oxygen, 1- ethylpropoxies, hexyloxy, 4- methyl amoxys, 3- methyl amoxys, 2- methyl amoxys, 1- methyl amoxys, 3, 3- dimethyl butyrate epoxides, 2, 2- dimethyl butyrate epoxides, 1, 1- dimethyl butyrate epoxides, 1, 2- dimethyl butyrate epoxides, 1, 3- dimethyl butyrate epoxides, 2, 3- dimethyl butyrates epoxide or 2- ethyl-butoxies, it is preferred that C₁-C₄Alkoxy base, and more preferably methoxy or ethoxy group.Particularly preferably methoxyl group.

Above-mentioned R¹Definition described in " halo-C₁-C₆- alkoxy base " is above-mentioned halogen atom and above-mentioned C₁-C₆Alkoxy bonding group and they can be fluorine methoxyl group, chloromethane epoxide, bromine methoxyl group, iodine methoxyl group, difluoro-methoxy, dichloro methoxyl group, dibromo methoxyl group, trifluoromethoxy, trichloromethoxy, 1- fluorine ethyoxyls, 2- fluorine ethyoxyls, 2- chloroethoxies, 2, 2, 2- trifluoro ethoxies, 2, 2, 2- tri-chloroethoxy bases, 3- fluorine propoxyl group, 3- bromine propoxyl group, 4- fluorine butoxy, 5- fluorine amoxy or 6- iodine hexyloxy groups, it is preferred that fluorine methoxyl group, chloromethane epoxide, difluoro-methoxy, dichloro methoxyl group, trifluoromethoxy, trichloromethoxy, 1- fluorine ethyoxyls, 2- fluorine ethyoxyls, 2- chloroethoxies or 2, 2, 2- trifluoro ethoxy groups, and more preferably fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy or 2, 2, 2- trifluoro ethoxy groups.Particularly preferably difluoro-methoxy.

Above-mentioned R¹Definition described in " C₁-C₆Alkylthio radicals " are above-mentioned " C₁-C₆The group of alkyl group " and sulfur atom linkage and they can be methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, butylthio, isobutylthio, secondary butylthio, tertiary butylthio, penta sulfenyl, isopentylthio, 2- methylbutylthios, new penta sulfenyl, 1- ethyl rosickyite bases, own sulfenyl, 4- methyl penta sulfenyls, 3- methyl penta sulfenyls, 2- methyl penta sulfenyls, 1- methyl penta sulfenyls, 3, 3- dimethyl butyrate sulfenyls, 2, 2- dimethyl butyrate sulfenyls, 1, 1- dimethyl butyrate sulfenyls, 1, 2- dimethyl butyrate sulfenyls, 1, 3- dimethyl butyrate sulfenyls, 2, 3- dimethyl butyrates sulfenyl or 2- ethyl butylthio groups, it is preferred that C₁-C₄Alkylthio radicals, and more preferably methyl mercapto or ethylmercapto group group.Particularly preferably methyl mercapto.

Above-mentioned R¹Definition described in " single C₁-C₆Alkylamino group " is above-mentioned " C₁-C₆The group of alkyl group " and amino bonded, they can be methylamino, ethylamino, the third amino, isopropylamino, fourth amino, i-butylamino, Zhong Ding amino, tertiary fourth amino, penta amino or own amino group, preferably list C₁-C₄Alkylamino group, and more preferably methylamino or ethylamino group.Particularly preferably methylamino.

Above-mentioned R¹Definition described in " two C₁-C₆Alkylamino group " can be such as dimethylamino, ethylmethylamino, methylpropylamino, isopropylmethylamino, butyl methyl amino, isobutyl methyl amino, sec-butyl methylamino, tertbutyl methyl amino, lignocaine, ethylpropylamino, ethylisopropylamino, dipropylamino, dibutylamino, dipentylamino or dihexyl amino group, preferably two C₁-C₄Alkylamino group, and more preferably dimethylamino or diethylamino group.Particularly preferably dimethylamino.

Above-mentioned R¹Definition described in " C₁-C₆Alkanoyl group " is the straight or branched alkanoyl of 1-6 carbon atom and can be formoxyl, acetyl group, propiono, bytyry, isobutyryl, valeryl (pentanoyl), valeryl, valeryl (valeryl) or isovaleryl group, preferably C₁-C₄Alkanoyl group, and more preferably formoxyl or acetyl group.

Above-mentioned R¹Definition described in " C₁-C₆Alkanoyl amido group " is the straight or branched alkanoyl amido group of 1-6 carbon atom and can be formamido group, acetylamino, propionamido, butyrylamino, isobutyryl amino, valeryl amino (pentanoylamino), pivaloyl amino, valeryl amino (valerylamino) or isoamyl amido groups, preferably C₁-C₄Alkanoyl amido group, and more preferably formamido group or acetamido group.

Above-mentioned R¹Definition described in " C₁-C₆Alkanoyloxy group " is the straight or branched alkanoyloxy group of 1-6 carbon atom and can be formyloxy, acetoxyl group, propionyloxy, butyryl acyloxy, isobutyl acyloxy, valeryl epoxide (pentanoyloxy), new pentane acyloxy, valeryl epoxide (valeryloxy) or isoamyl acyloxy group, preferably C₁-C₄Alkanoyloxy group, and more preferably formyloxy or acetoxyl group.

Above-mentioned R¹Definition described in " C₁-C₆Alkoxycarbonyl group " can be methoxycarbonyl group, carbethoxyl group, propylene carbonyl oxygen, butyloxycarbonyl, butoxy carbonyl, isobutyl boc, secondary butoxy carbonyl, tertbutyloxycarbonyl, penta oxygen carbonyl or own oxygen carbonyl group, preferably C₁-C₄Chain alkoxycarbonyl group, and more preferably methoxycarbonyl group or carbethoxyl group.Particularly preferably methoxycarbonyl group.

Above-mentioned R¹Definition described in " (C₁-C₆Alkylthio group) thiocarbonyl group " it is the thiocarbonyl group being bonded with the straight or branched alkylthio group of 1-6 carbon atom and can is (methyl mercapto) thiocarbonyl, (ethylmercapto group) thiocarbonyl, (rosickyite base) thiocarbonyl, (isopropyisulfanyl) thiocarbonyl, (butylthio) thiocarbonyl, (isobutylthio) thiocarbonyl, (secondary butylthio) thiocarbonyl, (tertiary butylthio) thiocarbonyl, (penta sulfenyl) thiocarbonyl or (own sulfenyl) thiocarbonyl group, preferably (C₁-C₄Alkylthio group) thiocarbonyl group, and more preferably (methyl mercapto) thiocarbonyl or (ethylmercapto group) thiocarbonyl.Most preferably (methyl mercapto) thiocarbonyl.

Above-mentioned R¹Definition described in " single C₁-C₆Alkyl-carbamoyl " group can be methylcarbamoyl, ethylaminocarbonyl, propvlcarbamovl, isopropylcarbamoyl, Butylcarbamoyl, butylcarbamoyl, s-butylamino formoxyl, t-Butylcarbamoyl, pentylcarbamoy or hexylamino formyl group, preferably list C₁-C₄Alkyl-carbamoyl group, and more preferably methylcarbamoyl or ethylaminocarbonyl.

Above-mentioned R¹Definition described in " two C₁-C₆Alkyl-carbamoyl group " can be formyl-dimethylamino, ethylmethylamino formoxyl, diethylamino formoxyl, dipropylamino formoxyl, diisopropylaminoethyl formoxyl, dibutylamino formoxyl, diisobutylamino formoxyl, di-sec-butyl carbamoyl, di-t-butyl carbamoyl, dipentylamino formoxyl or dihexyl carbamoyl group, preferably two C₁-C₄Alkyl-carbamoyl, and more preferably formyl-dimethylamino or diethylamino formoxyl.Particularly preferably formyl-dimethylamino.

It can be such as furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridine radicals, pyrazinyl, pyrimidine radicals or pyridazine basic ring " to contain 1 or 25 or 6 yuan of heteroaromatic for being selected from oxygen, nitrogen and sulfur heteroatom with isoxazole ring fusion " described in above-mentioned ring A definition, it is preferred that furyl, thienyl or pyridyl ring, and more preferably pyridyl ring.

Moreover, it is above-mentioned with furyl, the isoxazole compound of thienyl or pyridyl ring fusion be with following formula (III)-compound of structure shown in (XII).Preferably there is the compound of formula (III), (IV), (IX), (X), (XI) or (XII) structure, and more preferably there is the compound of formula (IX), (X), (XI) or (XII), it is further preferred that the compound with formula (IX) or (XII).Particularly preferably there is the compound of structure shown in formula (XII).

Above-mentioned R² _a" single C described in definition₁-C₄Alkylamino group " such as above-mentioned R¹Described in and particularly preferably methylamino.

Above-mentioned R² _a" two C described in definition₁-C₄Alkylamino group " such as above-mentioned R¹Described in and particularly preferably dimethylamino.

Above-mentioned R² _a" 5 or 6 circle heterocycles (condition is that the group is connected through relevant nitrogen-atoms) containing 1 nitrogen-atoms and arbitrarily containing another nitrogen-atoms or oxygen atom " can be such as pyrrole radicals, imidazole radicals, pyrazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl or morpholinyl group, preferably piperidyl or morpholinyl described in definition.

If R in formula (I) of the present invention and (II) compound¹It is basic group such as amino or alkylamino group, then can be converted into corresponding pharmaceutically acceptable salt by using acid treatment according to conventional methods.For example, at room temperature, solvent, which is evaporated off, in solvent (such as ethers, particularly dioxane), under the crystallization or decompression that are settled out by the compound (I) or (II) with corresponding acid treatment 5-30 minutes and through filtering can obtain salt.Such salt can be inorganic acid salt such as hydrochloride, hydrobromate, hydriodate, nitrate, perchlorate, sulfate or phosphate, sulfonate such as mesylate, fluoroform sulphonate, esilate, benzene sulfonate or tosilate, carboxylate such as fumarate, succinate, citrate, tartrate, oxalates and maleate, or amino-acid salt such as glutamate or aspartate.

If R in the compounds of this invention (I) and (II)¹It is acidic-group such as hydroxyl or carboxyl, then can be converted into corresponding pharmaceutically acceptable salt by using alkali process with conventional method.For example, at room temperature, in solvent (such as ethers, particularly ether or tetrahydrofuran) in, the compound (I) or (II) with corresponding alkali process 5-30 minutes and can be obtained into the compound (I) or the salt of (II) through filtering the crystallization being settled out or solvent being evaporated off under decompression.Such salt can be alkali metal salt such as sodium salt or sylvite, alkali salt such as calcium salt or magnesium salts, or organic amine salt such as guanidine, triethylamine or dicyclohexyl amine salt.

The compounds of this invention (I) or (II) or its salt when placing in atmosphere or in recrystallization can with moisture absorption, absorb water or become hydrate, and these salt for containing hydrone are also included within the scope of the present invention.

The compounds of this invention (I) or (II) or its salt can contain asymmetric carbon atom in the molecule thereof, therefore, it is possible to there is the stereoisomer of R- and S- conformations.These single compounds and the mixture existed with their any ratios are also included within the scope of the present invention.

Following compounds are preferred the compounds of this invention (I)；(1)R¹It is hydrogen, halogen, C₁-C₄Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2- fluoro ethyls, 2- chloroethyls, 2,2,2- trifluoroethyls, methoxy, methoxy ethyl, C₁-C₄Alkoxy, fluorine methoxyl group, chloromethane epoxide, difluoro-methoxy, dichloro methoxyl group, trifluoromethoxy, trichloromethoxy, 1- fluorine ethyoxyl, 2- fluorine ethyoxyl, 2- chloroethoxies, 2,2,2- trifluoro ethoxies, hydroxyl, C₁-C₄Alkylthio group, amino, list C₁-C₄Alkyl amino, two C₁-C₄Alkyl amino, formoxyl, acetyl group, formamido group, acetylamino, C₁-C₄Alkanoyloxy, C₁-C₄Alkoxy carbonyl group, carboxyl, (methyl mercapto) thiocarbonyl, (ethylmercapto group) thiocarbonyl, carbamoyl, methylcarbamoyl, ethylaminocarbonyl, formyl-dimethylamino, diethylamino formoxyl, the compound of nitro or cyano group.(2)R¹It is hydrogen, halogen, C₁-C₄Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2- fluoro ethyls, 2,2,2- trifluoroethyls, methoxy, methoxy ethyl, C₁-C₄Alkoxy, difluoro-methoxy, hydroxyl, C₁-C₄Alkylthio group, amino, methylamino, ethylamino, dimethylamino, lignocaine, formoxyl, acetyl group, formamido group, acetylamino, C₁-C₄Alkoxy carbonyl group, carboxyl, carbamoyl, methylcarbamoyl, ethylaminocarbonyl, formyl-dimethylamino, diethylamino formoxyl, the compound of nitro or cyano group.(3)R¹It is the compound of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxyl group, ethyoxyl, difluoro-methoxy, hydroxyl, methyl mercapto, ethylmercapto group, amino, methylamino, ethylamino, dimethylamino, formyloxy, acetoxyl group, methoxycarbonyl group, carbethoxyl group, carboxyl, carbamoyl, nitro or cyano group.(4)R¹It is the compound of hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group, methyl mercapto, difluoro-methoxy, methoxycarbonyl group, nitro or cyano group.(5) m is 2 compound.(6) m is 1 compound.(7) n is 2-4 compound.(8) n is 2 compound.(9) the ring A is the compound of phenyl, naphthyl, furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridine radicals, pyrazinyl, pyrimidine radicals or pyridazine basic ring.(10) the ring A is the compound of phenyl, naphthyl or pyridyl ring.(11) the ring A is the compound of phenyl or pyridyl ring.(12) the ring A is the compound of benzyl ring.(13) X is the compound of oxygen.(14) 3- (2- amino ethoxies) benzoisoxazole,

3- (2- aminoethanethios) benzoisoxazole,

3- (2- amino ethoxies)-fluorine benzoisoxazole,

3- (2- aminoethanethios)-fluorine benzoisoxazole,

3- (2- amino ethoxies)-fluoro-2-methyl benzoisoxazole,

3- (2- aminoethanethios)-fluoro-2-methyl benzoisoxazole,

3- (2- amino ethoxies)-fluoro- methyl mercapto benzoisoxazole,

3- (2- amino ethoxies)-fluoro- methoxycarbonyl group benzo isoxazole,

3- (2- amino ethoxies)-fluoro- carbamoyl benzoisoxazole,

3- (2- amino ethoxies)-fluoro- cyano group benzoisoxazole,

3- (2- aminoethanethios)-fluoro- cyano group benzoisoxazole,

3- (2- amino ethoxies)-Lv benzoisoxazoles,

3- (2- aminoethanethios)-Lv benzoisoxazoles,

3- (2- amino ethoxies)-dichloro benzoisoxazole,

3- (2- aminoethanethios)-dichloro benzoisoxazole,

3- (2- amino ethoxies)-chloro- methyl benzoisoxazole,

3- (2- aminoethanethios)-chloro- methyl benzoisoxazole,

3- (2- amino ethoxies)-chloro- carbamoyl benzoisoxazole,

3- (2- amino ethoxies)-chloro- cyano group benzoisoxazole,

3- (2- aminoethanethios)-chloro- cyano group benzoisoxazole,

3- (2- amino ethoxies)-dichloro-methyl benzoisoxazole,

3- (2- amino ethoxies)-bromine benzoisoxazole,

3- (2- amino ethoxies)-bromo- methyl benzoisoxazole,

3- (2- amino ethoxies)-methyl benzoisoxazole,

3- (2- aminoethanethios)-methyl benzoisoxazole,

3- (2- amino ethoxies)-dimethylbiphenyl isoxazole,

3- (2- amino ethoxies)-methyl-methoxyl group benzoisoxazole,

3- (2- amino ethoxies)-methyl-methylthio benzoisoxazole,

3- (2- amino ethoxies)-methyl-methoxycarbonyl group benzo isoxazole,

3- (2- amino ethoxies)-methyl-cabanaoyl benzoisoxazole,

3- (2- amino ethoxies)-methyl-cyano group benzoisoxazole,

3- (2- amino ethoxies)-trifluoromethyl benzo isoxazole,

3- (2- amino ethoxies)-methoxyl group benzoisoxazole,

3- (2- aminoethanethios)-methoxyl group benzoisoxazole,

3- (2- amino ethoxies)-difluoro-methoxy benzo isoxazole,

3- (2- amino ethoxies)-hydroxy benzo isoxazole,

3- (2- amino ethoxies)-amino benzoisoxazole,

3- (2- aminoethanethios)-amino benzoisoxazole,

3- (2- amino ethoxies)-methylamino benzoisoxazole,

3- (2- amino ethoxies)-dimethylamino benzo isoxazole,

3- (2- amino ethoxies)-acetoxyl group benzo isoxazole,

3- (2- amino ethoxies)-carboxyl benzoisoxazole,

3- (2- amino ethoxies)-methoxycarbonyl group benzo isoxazole,

3- (2- amino ethoxies)-carbamoyl benzoisoxazole,

3- (2- amino ethoxies)-nitro benzoisoxazole,

3- (2- aminoethanethios)-nitro benzoisoxazole,

3- (2- amino ethoxies)-cyano group benzoisoxazole,

3- (2- amino ethoxies)-naphthalene Bing isoxazoles,

3- (2- amino ethoxies)-pyrido isoxazole,

3- (2- amino ethoxies)-chloropyridine Bing isoxazoles,

3- (2- aminoethanethios)-chloropyridine Bing isoxazoles,

3- (2- amino ethoxies)-picoline Bing isoxazoles, or

3- (2- amino ethoxies)-trifluoromethyl pyridine Bing isoxazoles,

Any one of 1-5 kinds combination in (1)-(4), (5)-(6), (7)-(8), (9)-(12) and (13) group compound is also preferred, such as given following combination.(15) (1) and (7), (16) (2), (7) and (9), (17) (2), (8) and (10), (18) (3), (8) and (10), (19) (3), (5), (8) and (11), (20) (4), (8) and (10), (21) (4), (5), (8) and (11), (22) (4), (5), (8) and (12).

Following compounds are compound (II) of the preferred present invention as MAOI active component；(1)R¹It is hydrogen, halogen, C₁-C₄Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2- fluoro ethyls, 2- chloroethyls, 2,2,2- trifluoroethyls, methoxy, methoxy ethyl, C₁-C₄Alkoxy, fluorine methoxyl group, chloromethane epoxide, difluoro-methoxy, dichloro methoxyl group, trifluoromethoxy, trichloromethoxy, 1- fluorine ethyoxyl, 2- fluorine ethyoxyl, 2- chloroethoxies, 2,2,2- trifluoro ethoxies, hydroxyl, C₁-C₄Alkylthio group, amino, list C₁-C₄Alkyl amino, two C₁-C₄Alkyl amino, formoxyl, acetyl group, formamido group, acetylamino, C₁-C₄Alkanoyloxy, C₁-C₄Alkoxy carbonyl group, carboxyl, (methyl mercapto) thiocarbonyl, (ethylmercapto group) thiocarbonyl, carbamoyl, methylcarbamoyl, ethylaminocarbonyl, formyl-dimethylamino, diethylamino formoxyl, the compound of nitro or cyano group.(2)R¹It is hydrogen, halogen, C₁-C₄Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2- fluoro ethyls, 2,2,2- trifluoroethyls, methoxy, methoxy ethyl, C₁-C₄Alkoxy, difluoro-methoxy, hydroxyl, C₁-C₄Alkylthio group, amino, methylamino, ethylamino, dimethylamino, lignocaine, formoxyl, acetyl group, formamido group, acetylamino, C₁-C₄Alkoxy carbonyl group, carboxyl, carbamoyl, methylcarbamoyl, ethylaminocarbonyl, formyl-dimethylamino, diethylamino formoxyl, the compound of nitro or cyano group.(3)R¹It is the compound of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxyl group, ethyoxyl, difluoro-methoxy, hydroxyl, methyl mercapto, ethylmercapto group, amino, methylamino, ethylamino, dimethylamino, formyloxy, acetoxyl group, methoxycarbonyl group, carbethoxyl group, carboxyl, carbamoyl, nitro or cyano group.(4)R¹It is the compound of hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group, methyl mercapto, difluoro-methoxy, methoxycarbonyl group, nitro or cyano group.(5)R² _aIt is the compound of amino, methylamino, dimethylamino, piperidyl or morpholinyl group.(6)R² _aIt is the compound of amino, piperidyl or morpholinyl group.(7)R² _aIt is the compound of amino.(8) m is 2 compound.(9) m is 1 compound.(10) n is 2-4 compound.(11) n is 2 compound.(12) the ring A is the compound of phenyl, naphthyl, furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridine radicals, pyrazinyl, pyrimidine radicals or pyridazine basic ring.(13) the ring A is the compound of phenyl, naphthyl or pyridyl ring.(14) the ring A is the compound of phenyl or pyridyl ring.(15) the ring A is the compound of benzyl ring.(16) X is the compound of oxygen.(17) 3- (2- amino ethoxies) benzoisoxazole,

3- (2- aminoethanethios) benzoisoxazole,

3- (2- amino ethoxies)-fluorine benzoisoxazole,

3- (2- aminoethanethios)-fluorine benzoisoxazole,

3- (2- amino ethoxies)-fluoro-2-methyl benzoisoxazole,

3- (2- aminoethanethios)-fluoro-2-methyl benzoisoxazole,

3- (2- amino ethoxies)-fluoro- methyl mercapto benzoisoxazole,

3- (2- amino ethoxies)-fluoro- methoxycarbonyl group benzo isoxazole,

3- (2- amino ethoxies)-fluoro- carbamoyl benzoisoxazole,

3- (2- amino ethoxies)-fluoro- cyano group benzoisoxazole,

3- (2- aminoethanethios)-fluoro- cyano group benzoisoxazole,

3- (2- amino ethoxies)-Lv benzoisoxazoles,

3- (2- aminoethanethios)-Lv benzoisoxazoles,

3- (2- amino ethoxies)-dichloro benzoisoxazole,

3- (2- aminoethanethios)-dichloro benzoisoxazole,

3- (2- amino ethoxies)-chloro- methyl benzoisoxazole,

3- (2- aminoethanethios)-chloro- methyl benzoisoxazole,

3- (2- amino ethoxies)-chloro- carbamoyl benzoisoxazole,

3- (2- amino ethoxies)-chloro- cyano group benzoisoxazole,

3- (2- aminoethanethios)-chloro- cyano group benzoisoxazole,

3- (2- amino ethoxies)-dichloro-methyl benzoisoxazole,

3- (2- amino ethoxies)-bromine benzoisoxazole,

3- (2- amino ethoxies)-bromo- methyl benzoisoxazole,

3- (2- amino ethoxies)-methyl benzoisoxazole,

3- (2- aminoethanethios)-methyl benzoisoxazole,

3- (2- amino ethoxies)-dimethylbiphenyl isoxazole,

3- (2- amino ethoxies)-methyl-methoxyl group benzoisoxazole,

3- (2- amino ethoxies)-methyl-methylthio benzoisoxazole,

3- (2- amino ethoxies)-methyl-methoxycarbonyl group benzo isoxazole,

3- (2- amino ethoxies)-methyl-cabanaoyl benzoisoxazole,

3- (2- amino ethoxies)-methyl-cyano group benzoisoxazole,

3- (2- amino ethoxies)-trifluoromethyl benzo isoxazole,

3- (2- amino ethoxies)-methoxyl group benzoisoxazole,

3- (2- aminoethanethios)-methoxyl group benzoisoxazole,

3- (2- amino ethoxies)-difluoro-methoxy benzo isoxazole,

3- (2- amino ethoxies)-hydroxy benzo isoxazole,

3- (2- amino ethoxies)-amino benzoisoxazole,

3- (2- aminoethanethios)-amino benzoisoxazole,

3- (2- amino ethoxies)-methylamino benzoisoxazole,

3- (2- amino ethoxies)-dimethylamino benzo isoxazole,

3- (2- amino ethoxies)-acetoxyl group benzo isoxazole,

3- (2- amino ethoxies)-carboxyl benzoisoxazole,

3- (2- amino ethoxies)-methoxycarbonyl group benzo isoxazole,

3- (2- amino ethoxies)-carbamoyl benzoisoxazole,

3- (2- amino ethoxies)-nitro benzoisoxazole,

3- (2- aminoethanethios)-nitro benzoisoxazole,

3- (2- amino ethoxies)-cyano group benzoisoxazole,

3- (2- amino ethoxies)-naphthalene Bing isoxazoles,

3- (2- amino ethoxies)-pyrido isoxazole,

3- (2- amino ethoxies)-chloropyridine Bing isoxazoles,

3- (2- aminoethanethios)-chloropyridine Bing isoxazoles,

3- (2- amino ethoxies)-picoline Bing isoxazoles, or

3- (2- amino ethoxies)-trifluoromethyl pyridine Bing isoxazoles,

Any one of 1-6 kinds combination in (1)-(4), (5)-(7), (8)-(9), (10)-(11), (12)-(15) and (16) group compound is also preferred, such as given following combination.(17) (1), and (10) (5), (18) (2), (7), and (12) (10), (19) (2), (7), and (13) (11), (20) (3), (7), and (13) (11), (21) (3), (7), (8), and (14) (11), (22) (4), (7), and (13) (11), (23) (4), (7), (8), and (14) (11), (24) (4), (7), (8), and (15) (11).

Typical compound of the invention is the compound shown in following table, but is not limited only to these compounds.

Abbreviation used is as follows in table.

Ac：Acetyl group

Et：Ethyl

Me：Methyl

Ph：Phenyl

Pip：Piperidino

Prj：Isopropyl

Mor：Morpholino condition is (R¹)_mRepresent all 1 on ring A, 2 or 3 substituents.(table 1)(Ia) compound number (R¹)_m n X1-1 H 1 O1-2 H 1 S1-3 H 2 O1-4 H 2 S1-5 H 3 O1-6 H 3 S1-7 H 4 O1-8 H 4 S1-9 H 5 O1-10 H 5 S1-11 H 6 O1-12 H 6 S1-13 4-F 2 O1-14 4-F 2 S1-15 5-F 2 O1-16 5-F 4-F 2 O1-17 5-F 6-F 2 O1-18 5-F 7-F 2 O1-19 5-F 4-Cl 2 O1-20 5-F 6-Cl 2 O1-21 5-F 7-Cl 2 O1-22 5-F 4-Me 2 O1-23 5-F 6-Me 2 O1-24 5-F 7-Me 2 O1-25 5-F 4-OMe 2 O1-26 5-F 6-OMe 2 O1-27 5-F 7-OMe 2 O1-28 5-F 4-CN 2 O1-29 5-F 6-CN 2 O1-30 5-F 7-CN 2 O1-31 5-F 2 S1-32 5-F 4-F 2 S1-33 5-F 6-F 2 S1-34 5-F 7-F 2 S1-35 5-F 4-Cl 2 S1-36 5-F 6-Cl 2 S1-37 5-F 7-Cl 2 S1-38 5-F 4-Me 2 S1-39 5-F 6-Me 2 S1-40 5-F 7-Me 2 S1-41 5-F 4-OMe 2 S1-42 5-F 6-OMe 2 S1-43 5-F 7-OMe 2 S1-44 5-F 4-CN 2 S1-45 5-F 6-CN 2 S1-46 5-F 7-CN 2 S1-47 6-F 2 O1-48 6-F 2 S1-49 7-F 2 O1-50 7-F 2 S1-51 4-Cl 2 O1-52 4-Cl 2 S1-53 5-Cl 2 O1-54 5-Cl 4-F 2 O1-55 5-Cl 6-F 2 O1-56 5-Cl 7-F 2 O1-57 5-Cl 4-Cl 2 O1-58 5-Cl 6-Cl 2 O1-59 5-Cl 7-Cl 2 O1-60 5-Cl 4-Me 2 O1-61 5-Cl 6-Me 2 O1-62 5-Cl 7-Me 2 O1-63 5-Cl 4-OMe 2 O1-64 5-Cl 6-OMe 2 O1-65 5-Cl 7-OMe 2 O1-66 5-Cl 4-CN 2 O1-67 5-Cl 6-CN 2 O1-68 5-Cl 7-CN 2 O1-69 5-Cl 2 S1-70 5-Cl 4-F 2 S1-71 5-Cl 6-F 2 S1-72 5-Cl 7-F 2 S1-73 5-Cl 4-Cl 2 S1-74 5-Cl 6-Cl 2 S1-75 5-Cl 7-Cl 2 S1-76 5-Cl 4-Me 2 S1-77 5-Cl 6-Me 2 S1-78 5-Cl 7-Me 2 S1-79 5-Cl 4-OMe 2 S1-80 5-Cl 6-OMe 2 S1-81 5-Cl 7-OMe 2 S1-82 5-Cl 4-CN 2 S1-83 5-Cl 6-CN 2 S1-84 5-Cl 7-CN 2 S1-85 6-Cl 2 O1-86 6-Cl 7-Cl 2 O1-87 6-Cl 4-Me 2 O1-88 6-Cl 5-Me 2 O1-89 6-Cl 7-Me 2 O1-90 6-Cl 4-OMe 2 O1-91 6-Cl 5-OMe 2 O1-92 6-Cl 7-OMe 2 O1-93 6-Cl 4-CN 2 O1-94 6-Cl 5-CN 2 O1-95 6-Cl 7-CN 2 O1-96 6-Cl 2 S1-97 7-Cl 2 O1-98 7-Cl 4-Me 2 O1-99 7-Cl 5-Me 2 O1-100 7-Cl 6-Me 2 O1-101 7-Cl 4-OMe 2 O1-102 7-Cl 5-OMe 2 O1-103 7-Cl 6-OMe 2 O1-104 7-Cl 4-CN 2 O1-105 7-Cl 5-CN 2 O1-106 7-Cl 6-CN 2 O1-107 7-Cl 2 S1-108 7-Cl 4-Me 2 S1-109 7-Cl 5-Me 2 S1-110 7-Cl 6-Me 2 S1-111 7-Cl 4-OMe 2 S1-112 7-Cl 5-OMe 2 S1-113 7-Cl 6-OMe 2 S1-114 7-Cl 4-CN 2 S1-115 7-Cl 5-CN 2 S1-116 7-Cl 6-CN 2 S1-117 4-Br 2 O1-118 4-Br 2 S1-119 5-Br 2 O1-120 5-Br 4-F 2 O1-121 5-Br 6-F 2 O1-122 5-Br 7-F 2 O1-123 5-Br 4-Cl 2 O1-124 5-Br 6-Cl 2 O1-125 5-Br 7-Cl 2 O1-126 5-Br 4-Me 2 O1-127 5-Br 6-Me 2 O1-128 5-Br 7-Me 2 O1-129 5-Br 4-OMe 2 O1-130 5-Br 6-OMe 2 O1-131 5-Br 7-OMe 2 O1-132 5-Br 4-CN 2 O1-133 5-Br 6-CN 2 O1-134 5-Br 7-CN 2 O1-135 5-Br 2 S1-136 6-Br 2 O1-137 6-Br 2 S1-138 7-Br 2 O1-139 7-Br 2 S1-140 4-Me 2 O1-141 4-Me 2 S1-142 5-Me 2 O1-143 5-Me 6-Me 2 O1-144 5-M e 7-Me 2 O1-145 5-Me 4-OMe 2 O1-146 5-Me 6-OMe 2 O1-147 5-Me 7-OMe 2 O1-148 5-Me 4-CN 2 O1-149 5-Me 6-CN 2 O1-150 5-Me 7-CN 2 O1-151 5-Me 2 S1-152 5-Me 6-Me 2 S1-153 5-Me 7-Me 2 S1-154 5-Me 4-OMe 2 S1-155 5-Me 6-OMe 2 S1-156 5-Me 7-OMe 2 S1-157 5-Me 4-CN 2 S1-158 5-Me 6-CN 2 S1-159 5-Me 7-CN 2 S1-160 6-Me 2 O1-161 6-Me 7-Me 2 O1-162 6-Me 4-OMe 2 O1-163 6-Me 5-OMe 2 O1-164 6-Me 7-OMe 2 O1-165 6-Me 4-CN 2 O1-166 6-Me 5-CN 2 O1-167 6-Me 7-CN 2 O1-168 6-Me 2 S1-169 7-Me 2 O1-170 7-Me 4-OMe 2 O1-171 7-Me 5-OMe 2 O1-172 7-Me 6-OMe 2 O1-173 7-Me 4-CN 2 O1-174 7-Me 5-CN 2 O1-175 7-Me 6-CN 2 O1-176 7-Me 2 S1-177 7-Me 4-OMe 2 S1-178 7-Me 5-OMe 2 S1-179 7-Me 6-OMe 2 S1-180 7-Me 4-CN 2 S1-181 7-Me 5-CN 2 S1-182 7-Me 6-CN 2 S1-183 4-Et 2 O1-184 4-Et 2 S1-185 5-Et 2 O1-186 5-Et 2 S1-187 6-Et 2 O1-188 6-Et 2 S1-189 7-Et 2 O1-190 7-Et 2 S1-191 4-OMe 2 O1-192 4-OMe 2 S1-193 5-OMe 2 O1-194 5-OMe 4-CN 2 O1-195 5-OMe 6-CN 2 O1-196 5-OMe 7-CN 2 O1-197 5-OMe 2 S1-198 6-OMe 2 O1-199 6-OMe 2 S1-200 7-OMe 2 O1-201 7-OMe 4-Me 2 O1-202 7-OMe 5-OMe 2 O1-203 7-OMe 6-OMe 2 O1-204 7-OMe 4-CN 2 O1-205 7-OMe 5-CN 2 O1-206 7-OMe 6-CN 2 O1-207 7-OMe 2 S1-208 7-OMe 4-Me 2 S1-209 7-OMe 5-OMe 2 S1-210 7-OMe 6-Me 2 S1-211 7-OMe 4-CN 2 S1-212 7-OMe 5-CN 2 S1-213 7-OMe 6-CN 2 S1-214 4-OEt 2 O1-215 4-OEt 2 S1-216 5-OEt 2 O1-217 5-OEt 2 S1-218 6-OEt 2 O1-219 6-OEt 2 S1-220 7-OEt 2 O1-221 7-OEt 2 S1-222 4-OCHF₂ 2 O1-223 4-OCHF₂ 2 S1-224 5-OCHF₂ 2 O1-225 5-OCHF₂ 4-F 2 O1-226 5-OCHF₂ 6-F 2 O1-227 5-OCHF₂ 7-F 2 O1-228 5-OCHF₂ 4-Cl 2 O1-229 5-OCHF₂ 6-Cl 2 O1-230 5-OCHF₂ 7-Cl 2 O1-231 5-OCHF₂ 4-Me 2 O1-232 5-OCHF₂ 6-Me 2 O1-233 5-OCHF₂ 7-Me 2 O1-234 5-OCHF₂ 4-OMe 2 O1-235 5-OCHF₂ 6-OMe 2 O1-236 5-OCHF₂ 7-OMe 2 O1-237 5-OCHF₂ 4-CN 2 O1-238 5-OCHF₂ 6-CN 2 O1-239 5-OCHF₂ 7-CN 2 O1-240 5-OCHF₂ 2 S1-241 6-OCHF₂ 2 O1-242 6-OCHF₂ 2 S1-243 7-OCHF₂ 2 O1-244 7-OCHF₂ 2 S1-245 4-OH 2 O1-246 4-OH 2 S1-247 5-OH 2 O1-248 5-OH 4-F 2 O1-249 5-OH 6-F 2 O1-250 5-OH 7-F 2 O1-251 5-OH 4-Cl 2 O1-252 5-OH 6-Cl 2 O1-253 5-OH 7-Cl 2 O1-254 5-OH 4-Me 2 O1-255 5-OH 6-Me 2 O1-256 5-OH 7-Me 2 O1-257 5-OH 4-OMe 2 O1-258 5-OH 6-OMe 2 O1-259 5-OH 7-OMe 2 O1-260 5-OH 4-CN 2 O 1-261 5-OH 6-CN 2 O1-262 5-OH 7-CN 2 O1-263 5-OH 2 S1-264 6-OH 2 O1-265 6-OH 2 S1-266 7-OH 2 O1-267 7-OH 2 S1-268 4-SMe 2 O1-269 4-SMe 5-F 2 O1-270 4-SMe 6-F 2 O1-271 4-SMe 7-F 2 O1-272 4-SMe 5-Cl 2 O1-273 4-SMe 6-Cl 2 O1-274 4-SMe 7-Cl 2 O1-275 4-SMe 5-Me 2 O1-276 4-SMe 6-Me 2 O1-277 4-SMe 7-Me 2 O1-278 4-SMe 5-OMe 2 O1-279 4-SMe 6-OMe 2 O1-280 4-SMe 7-OMe 2 O1-281 4-SMe 5-CN 2 O1-282 4-SMe 6-CN 2 O1-283 4-SMe 7-CN 2 O1-284 4-SMe 2 S1-285 5-SMe 2 O1-286 5-SMe 2 S1-287 6-SMe 2 O1-288 6-SMe 2 S1-289 7-SMe 2 O1-290 7-SMe 2 S1-291 4-NH₂ 2 O1-292 4-NH₂ 2 S1-293 5-NH₂ 2 O1-294 5-NH₂ 2 S1-295 5-NH₂ 4-F 2 S1-296 5-NH₂ 6-F 2 S1-297 5-NH₂ 7-F 2 S1-298 5-NH₂ 4-Cl 2 S1-299 5-NH₂ 6-Cl 2 S1-300 5-NH₂ 7-Cl 2 S1-301 5-NH₂ 4-Me 2 S1-302 5-NH₂ 6-Me 2 S1-303 5-NH₂ 7-Me 2 S1-304 5-NH₂ 4-OMe 2 S1-305 5-NH₂ 6-OMe 2 S1-306 5-NH₂ 7-OMe 2 S1-307 5-NH₂ 4-CN 2 S1-308 5-NH₂ 6-CN 2 S1-309 5-NH₂ 7-CN 2 S1-310 6-NH₂ 2 O1-311 6-NH₂ 2 S1-312 7-NH₂ 2 O1-313 7-NH₂ 4-F 2 O1-314 7-NH₂ 5-F 2 O1-315 7-NH₂ 6-F 2 O1-316 7-NH₂ 4-Cl 2 O1-317 7-NH₂ 5-Cl 2 O1-318 7-NH₂ 6-Cl 2 O1-319 7-NH₂ 4-Me 2 O1-320 7-NH₂ 5-Me 2 O1-321 7-NH₂ 6-Me 2 O1-322 7-NH₂ 4-OMe 2 O1-323 7-NH₂ 5-OMe 2 O1-324 7-NH₂ 6-OMe 2 O1-325 7-NH₂ 4-CN 2 O1-326 7-NH₂ 5-CN 2 O1-327 7-NH₂ 6-CN 2 O1-328 7-NH₂ 2 S1-329 7-NH₂ 4-F 2 S1-330 7-NH₂ 5-F 2 S1-331 7-NH₂ 6-F 2 S1-332 7-NH₂ 4-Cl 2 S1-333 7-NH₂ 5-Cl 2 S1-334 7-NH₂ 6-Cl 2 S1-335 7-NH₂ 4-Me 2 S1-336 7-NH₂ 5-Me 2 S1-337 7-NH₂ 6-Me 2 S1-338 7-NH₂ 4-OMe 2 S1-339 7-NH₂ 5-OMe 2 S1-340 7-NH₂ 6-OMe 2 S1-341 7-NH₂ 4-CN 2 S1-342 7-NH₂ 5-CN 2 S1-343 7-NH₂ 6-CN 2 S1-344 4-NHMe 2 O1-345 4-NHMe 2 S1-346 5-NHMe 2 O1-347 5-NHMe 4-F 2 O1-348 5-NHMe 6-F 2 O1-349 5-NHMe 7-F 2 O1-350 5-NHMe 4-Cl 2 O1-351 5-NHMe 6-Cl 2 O1-352 5-NHMe 7-Cl 2 O1-353 5-NHMe 4-Me 2 O1-354 5-NHMe 6-Me 2 O1-355 5-NHMe 7-Me 2 O1-356 5-NHMe 4-OMe 2 O1-357 5-NHMe 6-OMe 2 O1-358 5-NHMe 7-OMe 2 O1-359 5-NHMe 4-CN 2 O1-360 5-NHMe 6-CN 2 O1-361 5-NHMe 7-CN 2 O1-362 5-NHMe 2 S1-363 6-NHMe 2 O1-364 6-NHMe 2 S1-365 7-NHMe 2 O1-366 7-NHMe 4-F 2 O1-367 7-NHMe 5-F 2 O1-368 7-NHMe 6-F 2 O1-369 7-NHMe 4-Cl 2 O1-370 7-NHMe 5-Cl 2 O1-371 7-NHMe 6-Cl 2 O1-372 7-NHMe 4-Me 2 O1-373 7-NHMe 5-Me 2 O1-374 7-NHMe 6-Me 2 O1-375 7-NHMe 4-OMe 2 O1-376 7-NHMe 5-OMe 2 O1-377 7-NHMe 6-OMe 2 O1-378 7-NHMe 4-CN 2 O1-379 7-NHMe 5-CN 2 O1-380 7-NHMe 6-CN 2 O1-381 7-NHMe 2 S1-382 4-OAc 2 O1-383 4-OAc 2 S1-384 5-OAc 2 O1-385 5-OAc 4-F 2 O1-386 5-OAc 6-F 2 O1-387 5-OAc 7-F 2 O1-388 5-OAc 4-Cl 2 O1-389 5-OAc 6-Cl 2 O1-390 5-OAc 7-Cl 2 O1-391 5-OAc 4-Me 2 O1-392 5-OAc 6-Me 2 O1-393 5-OAc 7-Me 2 O1-394 5-OAc 4-OMe 2 O1-395 5-OAc 6-OMe 2 O1-396 5-OAc 7-OMe 2 O1-397 5-OAc 4-CN 2 O1-398 5-OAc 6-CN 2 O1-399 5-OAc 7-CN 2 O1-400 5-OAc 2 S1-401 6-OAc 2 O1-402 6-OAc 2 S1-403 7-OAc 2 O1-404 7-OAc 2 S1-405 4-COOMe 2 O1-406 4-COOMe 5-F 2 O1-407 4-COOMe 6-F 2 O1-408 4-COOMe 7-F 2 O1-409 4-COOMe 5-Cl 2 O1-410 4-COOMe 6-Cl 2 O1-411 4-COOMe 7-Cl 2 O1-412 4-COOMe 5-Me 2 O1-413 4-COOMe 6-Me 2 O1-414 4-COOMe 7-Me 2 O1-415 4-COOMe 5-OMe 2 O1-416 4-COOMe 6-OMe 2 O1-417 4-COOMe 7-OMe 2 O1-418 4-COOMe 5-CN 2 O1-419 4-COOMe 6-CN 2 O1-420 4-COOMe 7-CN 2 O1-421 4-COOMe 2 S1-422 5-COOMe 2 O1-423 5-COOMe 4-F 2 O1-424 5-COOMe 6-F 2 O1-425 5-COOMe 7-F 2 O1-426 5-COOMe 4-Cl 2 O1-427 5-COOMe 6-Cl 2 O1-428 5-COOMe 7-Cl 2 O1-429 5-COOMe 4-Me 2 O1-430 5-COOMe 6-Me 2 O1-431 5-COOMe 7-Me 2 O1-432 5-COOMe 4-OMe 2 O1-433 5-COOMe 6-OMe 2 O1-434 5-COOMe 7-OMe 2 O1-435 5-COOMe 4-CN 2 O1-436 5-COOMe 6-CN 2 O1-437 5-COOMe 7-CN 2 O1-438 5-COOMe 2 S1-439 6-COOMe 2 O1-440 6-COOMe 2 S1-441 7-COOMe 2 O1-442 7-COOMe 4-F 2 O1-443 7-COOMe 5-F 2 O1-444 7-COOMe 6-F 2 O1-445 7-COOMe 4-Cl 2 O1-446 7-COOMe 5-Cl 2 O1-447 7-COOMe 5-Br 2 O1-448 7-COOMe 4-Me 2 O1-449 7-COOMe 5-Me 2 O1-50 7-COOMe 6-Me 2 O1-451 7-COOMe 4-OMe 2 O1-452 7-COOMe 5-OMe 2 O1-453 7-COOMe 6-OMe 2 O1-454 7-COOMe 4-CN 2 O1-455 7-COOMe 5-CN 2 O1-456 7-COOMe 6-CN 2 O1-457 7-COOMe 2 S1-458 4-COOH 2 O1-459 4-COOH 2 S1-460 5-COOH 2 O1-461 5-COOH 2 S1-462 6-COOH 2 O1-463 6-COOH 2 S1-464 7-COOH 2 O1-465 5-CF₃ 4-Me 2 O1-466 5-CF₃ 7-Me 2 O1-467 5-CF₃ 4-CN 2 O1-468 5-CF₃ 7-CN 2 O1-469 5-CF₃ 4-CF₃ 2 O1-470 5-CF₃ 7-CF₃ 2 O1-471 4-CF₃ 2 O1-472 4-CF₃ 5-Me 2 O1-473 4-CF₃ 5-F 2 O1-474 4-CF₃ 5-OMe 2 O1-475 4-CF₃ 5-SMe 2 O1-476 4-CF₃ 5-CN 2 O1-477 4-CF₃ 5-N(Me)₂ 2 O1-478 4-CF₃ 5-NO₂ 2 O1-479 4-CF₃ 5-Cl 2 O1-480 7-CF₃ 2 O1-481 4-CONH₂ 2 O1-482 4-CONH₂ 5-F 2 O1-483 4-CONH₂ 6-F 2 O1-484 4-CONH₂ 7-F 2 O1-485 4-CONH₂ 5-Cl 2 O1-486 4-CONH₂ 6-Cl 2 O1-487 4-CONH₂ 7-Cl 2 O1-488 4-CONH₂ 5-Me 2 O1-489 4-CONH₂ 6-Me 2 O1-490 4-CONH₂ 7-Me 2 O1-491 4-CONH₂ 5-OMe 2 O1-492 4-CONH₂ 6-OMe 2 O1-493 4-CONH₂ 7-OMe 2 O1-494 4-CONH₂ 5-CN 2 O1-495 4-CONH₂ 6-CN 2 O1-496 4-CONH₂ 7-CN 2 O1-497 4-CONH₂ 2 S1-498 5-CONH₂ 2 O1-499 5-CONH₂ 2 S1-500 6-CONH₂ 2 O1-501 6-CONH₂ 2 S1-502 7-CONH₂ 2 O1-503 5-SMe 4-Me 2 O1-504 5-SMe 5-CN 2 O1-505 5-SMe 7-Me 2 O1-506 5-SMe 7-CN 2 O1-507 5-CN 4-Me 2 O1-508 5-CN 4-CN 2 O1-509 7-CONH₂ 4-Me 2 O1-510 5-CN 7-CN 2 O1-511 7-CONH₂ 6-Me 2 O1-512 7-SMe 5-Cl 2 O1-513 7-SMe 5-Br 2 O1-514 7-SMe 5-NO₂ 2 O1-515 7-SMe 5-OMe 2 O1-516 7-SMe 5-CN 2 O1-517 7-SMe 4-CN 2 O1-518 7-CONH₂ 2 S1-519 4-NO₂ 2 O1-520 4-NO₂ 2 S1-521 5-NO₂ 2 O1-522 5-NO₂ 4-F 2 O1-523 5-NO₂ 6-F 2 O1-524 5-NO₂ 7-F 2 O1-525 5-NO₂ 4-Cl 2 O1-526 5-NO₂ 6-Cl 2 O1-527 5-NO₂ 7-Cl 2 O1-528 5-NO₂ 4-Me 2 O1-529 5-NO₂ 6-Me 2 O1-530 5-NO₂ 7-Me 2 O1-531 5-NO₂ 4-OMe 2 O1-532 5-NO₂ 6-OMe 2 O1-533 5-NO₂ 7-OMe 2 O1-534 5-NO₂ 4-CN 2 O1-535 5-NO₂ 6-CN 2 O1-536 5-NO₂ 7-CN 2 O1-537 5-NO₂ 2 S1-538 5-NO₂ 4-F 2 S1-539 5-NO₂ 6-F 2 S1-540 5-NO₂ 7-F 2 S1-541 5-NO₂ 4-Cl 2 S1-542 5-NO₂ 6-Cl 2 S1-543 5-NO₂ 7-Cl 2 S1-544 5-NO₂ 4-Me 2 S1-545 5-NO₂ 6-Me 2 S1-546 5-NO₂ 7-Me 2 S1-547 5-NO₂ 4-OMe 2 S1-548 5-NO₂ 6-OMe 2 S1-549 5-NO₂ 7-OMe 2 S1-550 5-NO₂ 4-CN 2 S1-551 5-NO₂ 6-CN 2 S1-552 5-NO₂ 7-CN 2 S1-553 6-NO₂ 2 O1-554 6-NO₂ 2 S1-555 7-NO₂ 2 O1-556 7-NO₂ 2 S1-557 7-NO₂ 4-F 2 S1-558 7-NO₂ 5-F 2 S1-559 7-NO₂ 6-F 2 S1-560 7-NO₂ 4-Cl 2 S1-561 7-NO₂ 5-Cl 2 S1-562 7-NO₂ 6-Cl 2 S1-563 7-NO₂ 4-Me 2 S1-564 7-NO₂ 5-Me 2 S1-565 7-NO₂ 6-Me 2 S1-566 7-NO₂ 4-OMe 2 S1-567 7-NO₂ 5-OMe 2 S1-568 7-NO₂ 6-OMe 2 S1-569 7-NO₂ 4-CN 2 S1-570 7-NO₂ 5-CN 2 S1-571 7-NO₂ 6-CN 2 S1-572 4-CN 2 O1-573 4-CN 2 S1-574 5-CN 2 O1-575 5-CN 2 S1-576 6-CN 2 O1-577 6-CN 2 S1-578 7-CN 2 O1-579 7-CN 2 S1-580 5-OMe 4-Me 2 O1-581 7-Me 4-Me 2 O1-582 6-Me 4-Me 2 O1-583 5-Me 4-Me 2 O1-584 4-N(Me)₂ 2 O1-585 4-N(Me)₂ 2 S1-586 5-N(Me)₂ 2 O1-587 5-N(Me)₂ 2 S1-588 6-N(Me)₂ 2 O1-589 6-N(Me)₂ 2 S1-590 7-N(Me)₂ 2 O1-591 7-N(Me)₂ 2 S1-592 4-Cl 6-Me 2 O1-593 4-Cl 6-Me 2 S1-594 4-F 5-Me 2 O1-595 4-F 5-Me 2 S1-596 4-F 7-Me 2 O1-597 4-F 7-Me 2 S1-598 5-Cl 7-CONH₂ 2 O1-599 5-Cl 7-CONH₂ 2 S1-600 5-F 4-CS₂Me 2 O1-601 5-F 4-CS₂Me 2 S1-602 5-F 4-CF₃ 2 S1-603 7-CF₃ 2 S1-604 4-F 7-Cl 2 O1-605 4-F 7-Cl 2 S1-606 4-F 7-CN 2 O1-607 4-F 7-CN 2 S1-608 7-F 4-Cl 2 O1-609 7-F 4-Cl 2 S1-610 7-F 4-Me 2 O1-611 7-F 4-Me 2 S1-612 7-F 4-CN 2 O1-613 7-F 4-CN 2 S1-614 4-Me 7-CN 2 O1-615 4-Me 7-CN 2 S1-616 5-F 7-F 4-Me 2 O1-617 5-F 7-F 4-Me 2 S1-618 5-Cl 7-Cl 4-Me 2 O1-619 5-Cl 7-Cl 4-Me 2 S1-620 5-Cl 7-Cl 4-COOH 2 O1-621 5-Cl 7-Cl 4-COOH 2 S1-622 5-Cl 7-Cl 4-COOMe 2 O1-623 5-Cl 7-Cl 4-COOMe 2 S1-624 5-Cl 7-Cl 4-CONH₂ 2 O1-625 5-Cl 7-Cl 4-CONH₂The S (table 2) of 2 S1-626 5-Cl 7-Cl 4-CN, 2 O1-627 5-Cl 7-Cl 4-CN 2Compound number (R¹)_m n X2-1 H 1 O2-2 H 1 S2-3 H 2 O2-4 4-F 2 O2-5 5-F 2 O2-6 6-F 2 O2-7 7-F 2 O2-8 8-F 2 O2-9 9-F 2 O2-10 4-Cl 2 O2-11 5-Cl 2 O2-12 6-Cl 2 O2-13 7-Cl 2 O2-14 8-Cl 2 O2-15 9-Cl 2 O2-16 5-NHMe 2 O2-17 6-NHMe 2 O2-18 7-NHMe 2 O2-19 4-Me 2 O2-20 5-Me 2 O2-21 6-Me 2 O2-22 7-Me 2 O2-23 8-Me 2 O2-24 9-Me 2 O2-25 5-N(Me)₂ 2 O2-26 6-N(Me)₂ 2 O2-27 7-N(Me)₂ 2 O2-28 8-N(Me)₂ 2 O2-29 4-OMe 2 O2-30 5-OMe 2 O2-31 6-OMe 2 O2-32 7-OMe 2 O2-33 8-OMe 2 O2-34 9-OMe 2 O2-35 5-OEt 2 O2-36 6-OEt 2 O2-37 7-OEt 2 O2-38 8-OEt 2 O2-39 5-OCHF₂ 2 O2-40 6-OCHF₂ 2 O2-41 7-OCHF₂ 2 O2-42 8-OCHF₂ 2 O2-43 5-NO₂ 2 O2-44 6-NO₂ 2 O2-45 7-NO₂ 2 O2-46 8-NO₂ 2 O2-47 4-CN 2 O2-48 5-CN 2 O2-49 6-CN 2 O2-50 7-CN 2 O2-51 8-CN 2 O2-52 9-CN 2 O2-53 H 2 S2-54 4-F 2 S2-55 5-F 2 S2-56 6-F 2 S2-57 7-F 2 S2-58 8-F 2 S2-59 9-F 2 S2-60 4-Cl 2 S2-61 5-Cl 2 S2-62 6-Cl 2 S2-63 7-Cl 2 S2-64 8-Cl 2 S2-65 9-Cl 2 S2-66 5-NHMe 2 S2-67 6-NHMe 2 S2-68 7-NHMe 2 S2-69 4-Me 2 S2-70 5-Me 2 S2-71 6-Me 2 S2-72 7-Me 2 S2-73 8-Me 2 S2-74 9-Me 2 S2-75 5-N(Me)₂ 2 S2-76 6-N(Me)₂ 2 S2-77 7-N(Me)₂ 2 S2-78 8-N(Me)₂ 2 S2-79 4-OMe 2 S2-80 5-OMe 2 S2-81 6-OMe 2 S2-82 7-OMe 2 S2-83 8-OMe 2 S2-84 9-OMe 2 S2-85 5-OEt 2 S2-86 6-OEt 2 S2-87 7-OEt 2 S2-88 8-OEt 2 S2-89 5-OCHF₂ 2 S2-90 6-OCHF₂ 2 S2-91 7-OCHF₂ 2 S2-92 8-OCHF₂ 2 S2-93 5-NO₂ 2 S2-94 6-NO₂ 2 S2-95 7-NO₂ 2 S2-96 8-NO₂The S (table 3) of 2 S2-97 4-CN, 2 S2-98 5-CN, 2 S2-99 6-CN, 2 S2-100 7-CN, 2 S2-101 8-CN, 2 S2-102 9-CN, 2 S2-103 H, 3 O2-104 H, 3 S2-105 H, 4 O2-106 H, 4 S2-107 H, 5 O2-108 H, 5 S2-109 H, 6 O2-110 H 6Compound number (R¹)_m n X3-1 H 1 O3-2 H 2 O3-3 H 2 S3-4 H 3 O3-5 4-F 2 O3-6 4-F 2 S3-7 4-F 3 O3-8 4-F 4 O3-9 5-F 2 O3-10 5-F 2 S3-11 5-F 3 O3-12 6-F 2 O3-13 6-F 2 S3-14 6-F 3 O3-15 4-Cl 2 O3-16 4-Cl 2 S3-17 4-Cl 3 O3-18 5-Cl 2 O3-19 5-Cl 2 S3-20 5-Cl 3 O3-21 6-Cl 2 O3-22 6-Cl 2 S3-23 6-Cl 3 O3-24 4-Cl 6-Cl 2 O3-25 4-Cl 6-Cl 2 S3-26 4-Br 2 O3-27 4-Br 2 S3-28 5-Br 2 O3-29 5-Br 2 S3-30 5-Br 3 O3-31 6-Br 2 O3-32 6-Br 2 S3-33 6-Br 3 O3-34 4-Br 6-Cl 2 O3-35 4-Br 6-Cl 2 S3-36 4-Me 2 O3-37 4-Me 2 S3-38 5-Me 2 O3-39 5-Me 2 S3-40 5-Me 3 O3-41 6-Me 2 O3-42 6-Me 2 S3-43 6-Me 3 O3-44 6-Me 4-Cl 2 O3-45 6-Me 4-Cl 2 S3-46 4-CN 2 O3-47 4-CN 2 S3-48 5-CN 2 O3-49 5-CN 2 S3-50 5-CN 3 O3-51 6-CN 2 O3-52 6-CN 2 S3-53 6-CN 3 O3-54 6-CN 4-Cl 2 O3-55 6-Et 4-Cl 2 S3-56 4-OMe 2 O3-57 4-OMe 2 S3-58 5-OMe 2 O3-59 5-OMe 2 S3-60 5-OMe 3 O3-61 6-OMe 2 O3-62 6-OMe 2 S3-63 6-OMe 3 O3-64 4-OEt 2 O3-65 4-OEt 2 S3-66 5-OEt 2 O3-67 5-OEt 2 S3-68 5-OEt 3 O3-69 6-OEt 2 O3-70 6-OEt 2 S3-71 6-OEt 3 O3-72 4-NO₂ 2 O3-73 4-NO₂ 2 S3-74 4-NO₂ 3 O3-75 5-NO₂ 2 O3-76 5-NO₂ 2 S3-77 5-NO₂ 3 O3-78 6-NO₂ 2 O3-79 6-NO₂ 2 S3-80 6-NO₂ 3 O3-81 4-NO₂ 6-Cl 2 O3-82 4-NO₂ 6-Cl 2 S3-83 4-CF₃ 2 O3-84 4-CF₃ 2 S3-85 5-CF₃ 2 O3-86 5-CF₃ 2 S3-87 5-CF₃ 3 O3-88 6-CF₃ 2 O3-89 6-CF₃ 2 S3-90 6-CF₃3 O (table 4)Compound number (R¹)_m n X4-1 H 1 O4-2 H 2 O4-3 H 2 S44 H 3 O4-5 5-F 2 O4-6 5-F 2 S4-7 5-F 3 O4-8 6-F 2 O4-9 6-F 2 S4-10 6-F 3 O4-11 7-Cl 2 O4-12 7-Cl 2 S4-13 7-Cl 3 O4-14 5-Cl 2 O4-15 5-Cl 2 S4-16 5-Cl 3 O4-17 6-Cl 2 O4-18 6-Cl 2 S4-19 6-Cl 3 O4-20 7-Br 2 O4-21 7-Br 2 S4-22 5-Br 2 O4-23 5-Br 2 S4-24 5-Br 3 O4-25 6-Br 2 O4-26 6-Br 2 S4-27 6-Br 3 O4-28 7-Br 6-Cl 2 O4-29 7-Br 6-Cl 2 S4-30 7-Me 2 O4-31 7-Me 2 S4-32 5-Me 2 O4-33 5-Me 2 S4-34 5-Me 3 O4-35 6-Me 2 O4-36 6-Me 2 S4-37 6-Me 3 O4-38 6-Me 7-Cl 2 O4-39 6-Me 7-Cl 2 S4-40 7-CN 2 O4-41 7-CN 2 S4-42 5-CN 2 O4-43 5-CN 2 S4-44 5-CN 3 O4-45 6-CN 2 O4-46 6-CN 2 S4-47 6-CN 3 O4-48 6-CN 7-Cl 2 O4-49 6-Et 7-Cl 2 S4-50 7-OMe 2 O4-51 7-OMe 2 S4-52 5-OMe 2 O4-53 5-OMe 2 S4-54 5-OMe 3 O4-55 6-OMe 2 O4-56 6-OMe 2 S4-57 6-OMe 3 O4-58 7-OEt 2 O4-59 7-OEt 2 S4-60 5-OEt 2 O4-61 5-OEt 2 S4-62 5-OEt 3 O4-63 6-OEt 2 O4-64 6-OEt 2 S4-65 6-OEt 3 O4-66 7-NO₂ 2 O4-67 7-NO₂ 2 S4-68 7-NO₂ 3 O4-69 5-NO₂ 2 O4-70 5-NO₂ 2 S4-71 5-NO₂ 3 O4-72 6-NO₂ 2 O4-73 6-NO₂ 2 S4-74 6-NO₂ 3 O4-75 7-NO₂ 6-Cl 2 O4-76 7-NO₂The S of 6-Cl 2 (table 5)Compound number (R¹)_m n X5-1 H 1 O5-2 H 2 O5-3 H 2 S5-4 H 3 O5-5 4-F 2 O5-6 4-F 2 S5-7 4-F 3 O5-8 6-F 2 O5-9 6-F 2 S5-10 6-F 3 O5-11 7-Cl 2 O5-12 7-Cl 2 S5-13 7-Cl 3 O5-14 4-Cl 2 O5-15 4-Cl 2 S5-16 4-Cl 3 O5-17 6-Cl 2 O5-1 8 6-Cl 2 S5-19 6-Cl 3 O5-20 7-Br 2 O5-21 7-Br 2 S5-22 4-Br 2 O5-23 4-Br 2 S5-24 4-Br 3 O5-25 6-Br 2 O5-26 6-Br 2 S5-27 6-Br 3 O5-28 7-Br 6-Cl 2 O5-29 7-Br 6-Cl 2 S5-30 7-Me 2 O5-31 7-Me 2 S5-32 4-Me 2 O5-33 4-Me 2 S5-34 4-Me 3 O5-35 6-Me 2 O5-36 6-Me 2 S5-37 6-Me 3 O5-38 6-Me 7-Cl 2 O5-39 6-Me 7-Cl 2 S5-40 7-CN 2 O5-41 7-CN 2 S5-42 4-CN 2 O5-43 4-CN 2 S5-44 4-CN 3 O5-45 6-CN 2 O5-46 6-CN 2 S5-47 6-CN 3 O5-48 6-CN 7-Cl 2 O5-49 6-Et 7-Cl 2 S5-50 7-OMe 2 O5-51 7-OMe 2 S5-52 4-OMe 2 O5-53 4-OMe 2 S5-54 4-OMe 3 O5-55 6-OMe 2 O5-56 6-OMe 2 S5-57 6-OMe 3 O5-58 7-OEt 2 O5-59 7-OEt 2 S5-60 4-OEt 2 O5-61 4-OEt 2 S5-62 4-OEt 3 O5-63 6-OEt 2 O5-64 6-OEt 2 S5-65 6-OEt 3 O5-66 7-NO₂ 2 O5-67 7-NO₂ 2 S5-68 7-NO₂ 3 O5-69 4-NO₂ 2 O5-70 4-NO₂ 2 S5-71 4-NO₂ 3 O5-72 6-NO₂ 2 O5-73 6-NO₂ 2 S5-74 6-NO₂ 3 O5-75 7-NO₂ 6-Cl 2 O5-76 7-NO₂The S of 6-Cl 2 (table 6)

Compound number (R¹)_m n X6-1 H 1 O6-2 H 2 O6-3 H 2 S6-4 H 3 O6-5 4-F 2 O6-6 4-F 2 S6-7 4-F 3 O6-8 5-F 2 O6-9 5-F 2 S6-10 5-F 3 O6-11 7-Cl 2 O6-12 7-Cl 2 S6-13 7-Cl 3 O6-14 4-Cl 2 O6-15 4-Cl 2 S6-16 4-Cl 3 O6-17 5-Cl 2 O6-18 5-Cl 2 S6-19 5-Cl 3 O6-20 7-Br 2 O6-21 7-Br 2 S6-22 4-Br 2 O6-23 4-Br 2 S6-24 4-Br 3 O6-25 5-Br 2 O6-26 5-Br 2 S6-27 5-Br 3 O6-28 7-Br 5-Cl 2 O6-29 7-Br 5-Cl 2 S6-30 7-Me 2 O6-31 7-Me 2 S6-32 4-Me 2 O6-33 4-Me 2 S6-34 4-Me 3 O6-35 5-Me 2 O6-36 5-Me 2 S6-37 5-Me 3 O6-38 5-Me 7-Cl 2 O6-39 5-Me 7-Cl 2 S6-40 7-CN 2 O6-41 7-CN 2 S6-42 4-CN 2 O6-43 4-CN 2 S6-44 4-CN 3 O6-45 5-CN 2 O6-46 5-CN 2 S6-47 5-CN 3 O6-48 5-CN 7-Cl 2 O6-49 5-Et 7-Cl 2 S6-50 7-OMe 2 O6-51 7-OMe 2 S6-52 4-OMe 2 O6-53 4-OMe 2 S6-54 4-OMe 3 O6-55 5-OMe 2 O6-56 5-OMe 2 S6-57 5-OMe 3 O6-58 7-OEt 2 O6-59 7-OEt 2 S6-60 4-OEt 2 O6-61 4-OEt 2 S6-62 4-OEt 3 O6-63 5-OEt 2 O6-64 5-OEt 2 S6-65 5-OEt 3 O6-66 7-NO₂ 2 O6-67 7-NO₂ 2 S6-68 7-NO₂ 3 O6-69 4-NO₂ 2 O6-70 4-NO₂ 2 S6-71 4-NO₂ 3 O6-72 5-NO₂ 2 O6-73 5-NO₂ 2 S6-74 5-NO₂ 3 O6-75 7-NO₂ 5-Cl 2 O6-76 7-NO₂The S of 5-Cl 2 (table 7)

Compound number (R¹)_m n X7-1 H 2 O7-2 H 2 S7-3 5-F 2 O7-4 5-F 2 S7-5 6-F 2 O7-6 6-F 2 S7-7 5-Cl 2 O7-8 5-Cl 2 S7-9 6-Cl 2 O7-10 6-Cl 2 S7-11 6-Cl 3 O7-12 5-Br 2 O7-13 5-Br 2 S7-14 6-Br 2 O7-15 6-Br 2 S7-16 5-Me 2 O7-17 5-Me 2 S7-18 6-Me 2 O7-19 6-Me 2 S7-20 5-Et 2 O7-21 5-Et 2 S7-22 6-Et 2 O7-23 6-Et 2 S7-24 5-OMe 2 O7-25 5-OMe 2 S7-26 6-OMe 2 O7-27 6-OMe 2 S7-28 5-OEt 2 O7-29 5-OEt 2 S7-30 6-OEt 2 O7-31 6-OEt 2 S7-32 5-NO₂ 2 O7-33 5-NO₂ 2 S7-34 6-NO₂ 2 O7-35 6-NO₂2 S (table 8)Compound number (R¹)_m n X8-1 H 2 O8-2 H 2 S8-3 4-F 2 O8-4 4-F 2 O8-5 5-F 2 O8-6 5-F 2 S8-7 4-Cl 2 O8-8 5-Cl 2 O8-9 4-Br 2 O8-10 4-Br 2 S8-11 5-Br 2 O8-12 5-Br 2 S8-13 4-Me 2 O8-14 4-Me 2 S8-15 5-Me 2 O8-16 5-Me 2 S8-17 4-Et 2 O8-18 4-Et 2 S8-19 5-Et 2 O8-20 5-Et 2 S8-21 4-OMe 2 O8-22 4-OMe 2 S8-23 5-OMe 2 O8-24 5-OMe 2 S8-25 4-OEt 2 O8-26 4-OEt 2 S8-27 5-OEt 2 O8-28 5-OEt 2 S8-29 4-NO₂ 2 O8-30 4-NO₂ 2 S8-31 5-NO₂ 2 O8-32 5-NO₂2 S (table 9)

Compound number (R¹)_m n R² _b X9-1 H 2 NHMe O9-2 H 2 NMe₂ O9-3 H 2 Pip O9-4 H 2 Mor O9-5 H 2 NHMe S9-6 H 2 NMe₂ S9-7 H 2 Pip S9-8 H 2 Mor S9-9 4-F 2 Pip O9-10 4-F 2 Mor O9-11 4-F 2 Pip S9-12 4-F 2 Mor S9-13 5-F 2 NHMe O9-14 5-F 2 NMe₂ O9-15 5-F 2 Pip O9-16 5-F 2 Mor O9-17 5-F 2 NHMe S9-18 5-F 2 NMe₂ S9-19 6-F 2 NHMe O9-20 6-F 2 NMe₂ O9-22 6-F 2 Mor O9-23 6-F 2 NHMe S9-24 6-F 2 NMe₂ S9-25 7-F 2 NHMe O9-26 7-F 2 NMe₂ O9-27 7-F 2 Pip O9-28 7-F 2 Mor O9-29 5-F 7-Cl 2 NHMe O9-30 5-F 7-Cl 2 NMe₂ O9-31 5-F 7-Cl 2 Pip O9-32 5-F 7-Cl 2 Mor O9-33 5-F 7-Cl 2 NHMe S9-34 5-F 7-Cl 2 NMe₂ S9-35 7-F 5-Cl 2 Pip O9-36 7-F 5-Cl 2 Mor O9-37 4-Cl 2 NHe O9-38 4-Cl 2 NMe₂ O9-39 4-Cl 2 Pip O9-40 4-Cl 2 Mor O9-41 4-Cl 2 NHMe S9-42 4-Cl 2 NMe₂ S9-43 5-Cl 2 NHMe O9-44 5-Cl 2 NMe₂ O9-45 5-Cl 2 Pip O9-46 5-Cl 2 Mor O9-47 5-Cl 2 NHMe S9-48 5-Cl 2 NMe₂ S9-49 6-Cl 2 NHMe O9-50 6-Cl 2 NMe₂ O9-51 6-Cl 2 Pip O9-52 6-Cl 2 Mor O9-53 7-Cl 2 NHMe O9-54 7-Cl 2 NMe₂ O9-55 7-Cl 2 Pip O9-56 7-Cl 2 Mor O9-57 4-Cl 6-Cl 2 NHMe O9-58 4-Cl 6-Cl 2 NMe₂ O9-59 4-Cl 6-Cl 2 Pip O9-60 4-Cl 6-Cl 2 Mor O9-61 5-Cl 7-Cl 2 NHMe O9-62 5-Cl 7-Cl 2 NMe₂ O9-63 5-Cl 7-Cl 2 Pip O9-64 5-Cl 7-Cl 2 Mor O9-65 5-Cl 7-Cl 2 NHMe S9-66 5-Cl 7-Cl 2 NMe₂ S9-67 5-Cl 7-Cl 2 Pip S9-68 5-Cl 7-Cl 2 Mor S9-69 4-Br 2 Pip O9-70 5-Br 2 NHMe O9-71 5-Br 2 NMe₂ O9-72 5-Br 2 Pip O9-73 5-Br 2 Mor O9-74 6-Br 2 NHMe O9-75 6-Br 2 NMe₂ O9-76 6-Br 2 Pip O9-77 6-Br 2 Mor O9-78 7-Br 2 NHMe O9-79 7-Br 2 NMe₂ O9-80 7-Br 2 Pip O9-81 7-Br 2 Mor O9-82 4-Br 6-Cl 2 Pip O9-83 5-Br 7-Cl 2 Pip O9-84 4-Me 2 NHMe O9-85 4-Me 2 NMe₂ O9-86 4-Me 2 Pip O9-87 4-Me 2 Mor O9-88 5-Me 2 NHMe O9-89 5-Me 2 NMe₂ O9-90 5-Me 2 Pip O9-91 5-Me 2 Mor O9-92 5-Me 2 NHMe S9-93 5-Me 2 NMe₂ S9-94 5-Me 2 Pip S9-95 5-Me 2 Mor S9-96 6-Me 2 NHMe O9-97 6-Me 2 NMe₂ O9-98 6-Me 2 PiP O9-99 6-Me 2 Mor O9-100 7-Me 2 NHMe O9-101 7-Me 2 NMe₂ O9-102 7-Me 2 Pip O9-103 7-Me 2 Mor O9-104 5-Me 7-Cl 2 PiP O9-105 5-Me 7-Cl 2 Pip S9-106 6-Me 4-Cl 2 Pip O9-107 7-Me 5-Cl 2 Pip O9-108 7-Me 5-Cl 2 Pip S9-109 4-Et 2 Pip O9-110 4-Et 2 Mor O9-111 5-Et 2 Pip O9-112 5-Et 2 Mor O9-113 6-Et 2 Pip O9-114 6-Et 2 Mor O9-115 7-Et 2 Pip O9-116 7-Et 2 Mor O9-117 5-Et 7-Cl 2 Mor O9-118 6-Et 4-Cl 2 Mor O9-119 7-Et 5-Cl 2 Mor O9-120 4-OMe 2 NHMe O9-121 4-OMe 2 NMe₂ O9-122 4-OMe 2 Pip O9-123 4-OMe 2 Mor O9-124 4-OMe 2 NHMe S9-125 4-OMe 2 NMe₂ S9-126 4-OMe 2 pip S9-127 4-OMe 2 Mor S9-128 5-OMe 2 NHMe O9-129 5-OMe 2 NMe₂ O9-130 5-OMe 2 Pip O9-131 5-OMe 2 Mor O9-132 5-OMe 2 NHMe S9-133 5-OMe 2 NMe₂ S9-134 5-OMe 2 Pip S9-135 5-OMe 2 Mor S9-136 6-OMe 2 NHMe O9-137 6-OMe 2 NMe₂ O9-138 6-OMe 2 Pip O9-139 6-OMe 2 Mor O9-140 7-OMe 2 NHMe O9-141 7-OMe 2 NMe₂ O9-142 7-OMe 2 Pip O9-143 7-OMe 2 Mor O9-144 5-OMe 7-Cl 2 Pip O9-145 7-OMe 5-Cl 2 Pip O9-146 4-OEt 2 Pip O9-147 4-OEt 2 Mor O9-148 5-OEt 2 Pip O9-149 5-OEt 2 Mor O9-150 6-OEt 2 Pip O9-151 6-OEt 2 Mor O9-152 7-OEt 2 Pip O9-153 7-OEt 2 Mor O9-154 5-OEt 7-Cl 2 Mor O9-155 7-OEt 5-Cl 2 Mor O9-156 4-NO2 2 NHMe O9-157 4-NO2 2 NMe₂ O9-158 4-NO₂ 2 Pip O9-159 4-NO₂ 2 Mor O9-160 4-NO₂ 2 NHMe S9-161 4-NO₂ 2 NMe₂ S9-162 4-NO₂ 2 Pip S9-163 4-NO₂ 2 Mor S9-164 5-NO₂ 2 NHMe O9-165 5-NO₂ 2 NMe₂ O9-166 5-NO₂ 2 Pip O9-167 5-NO₂ 2 Mor O9-168 5-NO₂ 2 NHMe S9-169 5-NO₂ 2 NMe₂ S9-170 5-NO₂ 2 Pip S9-171 5-NO₂ 2 Mor S9-172 6-NO₂ 2 NHMe O9-173 6-NO₂ 2 NMe₂ O9-174 6-NO₂ 2 Pip O9-175 6-NO₂ 2 Mor O9-176 7-NO₂ 2 NHMe O9-177 7-NO₂ 2 NMe₂ O9-178 7-NO₂ 2 Pip O9-179 7-NO₂ 2 Mor O9-180 4-NO₂ 6-Cl 2 Pip O9-181 5-NO₂ 7-Cl 2 Pip O9-182 5-NO₂The Pip S of 7-Cl 2 (table 10)Compound number (R¹)_m n R² _b X10-1 H 2 NHMe O10-2 H 2 NMe₂ O10-3 H 2 Pip O10-4 H 2 Mor O10-5 H 2 NHMe S10-6 H 2 NMe₂ S10-7 H 2 Pip S10-8 H 2 Mor S10-9 4-F 2 NHMe O10-10 5-F 2 NMe₂ O10-11 6-F 2 Pip O10-12 7-F 2 Mor O10-13 8-F 2 Pip O10-14 9-F 2 Mor O10-15 5-F 2 NMe₂ S10-16 6-F 2 Pip S10-17 7-F 2 Mor S10-18 8-F 2 Pip S10-19 5-Cl 2 NMe₂ O10-20 6-Cl 2 Pip O10-21 7-Cl 2 Mor O10-22 8-Cl 2 Pip O10-23 5-Cl 2 NMe₂ S10-24 6-Cl 2 Pip S10-25 7-Cl 2 Mor S10-26 8-Cl 2 Pip S10-27 8-Br 2 Pip O10-28 5-Br 2 NMe₂ S10-29 5-Me 2 NMe₂ O10-30 6-Me 2 Pip O10-31 7-Me 2 Mor O10-32 8-Me 2 Pip O10-33 5-Me 2 NMe₂ S10-34 6-Me 2 Pip S10-35 7-Me 2 Mor S10-36 8-Me 2 Pip S10-37 8-Et 2 Pip O10-38 5-Et 2 NMe₂ S10-39 5-OMe 2 NMe₂ O10-40 6-OMe 2 Pip O10-41 7-OMe 2 Mor O10-42 8-OMe 2 Pip O10-43 5-OMe 2 NMe₂ S10-44 6-OMe 2 Pip S10-45 7-OMe 2 Mor S10-46 8-OMe 2 Pip S10-47 8-OEt 2 Pip O10-48 5-OEt 2 NMe₂ S10-49 8-OCHF₂ 2 Pip O10-50 5-OCHF₂ 2 NMe₂ S10-51 5-NO₂ 2 NMe₂ O10-52 6-NO₂ 2 Pip O10-53 7-NO₂ 2 Mor O10-54 8-NO₂ 2 Pip O10-55 5-NO₂ 2 NMe₂ S10-56 6-NO₂ 2 Pip S10-57 7-NO₂ 2 Mor S10-58 8-NO₂ 2 Pip S10-59 5-CN 2 NMe₂ O10-60 6-CN 2 Pip O10-61 7-CN 2 Mor O10-62 8-CN 2 Pip O10-63 5-CN 2 NMe₂The Pip S (table 11) of 2 Pip S10-65 7-CN of S10-64 6-CN, 2 Mor S10-66 8-CN 2Compound number (R¹)_m n R₂ ^b X11-1 H 2 NHMe O11-2 H 2 NMe₂ O11-3 H 2 Pip O11-4 H 2 Mor O11-5 H 2 NHMe S11-6 H 2 NMe₂ S11-7 H 2 Pip S11-8 H 2 Mor S11-9 4-F 2 Pip O11-10 4-F 2 Mor O11-11 4-F 2 Pip S11-12 4-F 2 Mor S11-13 5-F 2 NHMe O11-14 5-F 2 NMe₂ O11-15 5-F 2 Pip O11-16 5-F 2 Mor O11-17 5-F 2 NHMe S11-18 5-F 2 NMe₂ S11-19 6-F 2 NHMe O11-20 6-F 2 NMe₂ O11-21 6-F 2 Pip O11-22 6-F 2 Mor O11-23 4-Cl 2 NHMe O11-24 4-Cl 2 NMe₂ O11-25 4-Cl 2 Pip O11-26 4-Cl 2 Mor O11-27 4-Cl 2 NHMe S11-28 4-Cl 2 NMe₂ S11-29 5-Cl 2 NHMe O11-30 5-Cl 2 NMe₂ O11-31 5-Cl 2 Pip O11-32 5-Cl 2 Mor O11-33 5-Cl 2 NHMe S11-34 5-Cl 2 NMe₂ S11-35 5-Cl 2 Pip S11-36 5-Cl 2 Mor S11-37 6-Cl 2 NHMe O11-38 6-Cl 2 NMe₂ O11-39 6-Cl 2 Pip O11-40 6-Cl 2 Mor O11-41 4-Cl 6-Cl 2 NHMe O11-42 4-Cl 6-Cl 2 NMe₂ O11-43 4-Cl 6-Cl 2 Pip O11-44 4-Br 2 Mor O11-45 5-Br 2 NHMe O11-46 5-Br 2 NMe₂ O11-47 5-Br 2 Pip O11-48 5-Br 2 Mor O11-49 5-Br 2 NHMe S11-50 5-Br 2 NMe₂ S11-51 6-Br 2 NHMe O11-52 6-Br 2 NMe₂ O11-53 6-Br 2 Pip O11-54 6-Br 2 Mor O11-55 4-Br 6-Cl 2 Pip O11-56 4-Me 2 NHMe O11-57 4-Me 2 NMe₂ O11-58 4-Me 2 Pip O11-59 4-Me 2 Mor O11-60 4-Me 2 NHMe S11-61 4-Me 2 NMe₂ S11-62 4-Me 2 Pip S11-63 4-Me 2 Mor S11-64 5-Me 2 NHMe O11-65 5-Me 2 NMe₂ O11-66 5-Me 2 Pip O11-67 5-Me 2 Mor O11-68 5-Me 2 NHMe S11-69 5-Me 2 NMe₂ S11-70 6-Me 2 NHMe O11-71 6-Me 2 NMe₂ O11-72 6-Me 2 Pip O11-73 6-Me 2 Mor O11-74 6-Me 4-Cl 2 Pip O11-75 4-Et 2 Pip O11-76 4-Et 2 Mor O11-77 5-Et 2 Pip O11-78 5-Et 2 Mor O11-79 5-Et 2 Pip S11-80 5-Et 2 Mor S11-81 6-Et 2 Pip O11-82 6-Et 2 Mor O11-83 6-Et 4-Cl 2 Mor O11-84 4-OMe 2 NHMe O11-85 4-OMe 2 NMe₂ O11-86 4-OMe 2 Pip O11-87 4-OMe 2 Mor O11-88 4-OMe 2 NHMe S11-89 4-OMe 2 NMe₂ S11-90 4-OMe 2 Pip S11-91 4-OMe 2 Mor S11-92 5-OMe 2 NHMe O11-93 5-OMe 2 NMe₂ O11-94 5-OMe 2 Pip O11-95 5-OMe 2 Mor O11-96 5-OMe 2 NHMe S11-97 5-OMe 2 NMe₂ S11-98 5-OMe 2 Pip S11-99 5-OMe 2 Mor S11-100 6-OMe 2 NHMe O11-101 6-OMe 2 NMe₂ O11-102 6-OMe 2 Pip O11-103 6-OMe 2 Mor O11-104 4-OEt 2 Pip O11-105 4-OEt 2 Mor O11-106 4-OEt 2 Pip S11-107 4-OEt 2 Mor S11-108 5-OEt 2 Pip O11-109 5-OEt 2 Mor O11-110 5-OEt 2 Pip S11-111 5-OEt 2 Mor S11-112 6-OEt 2 Pip O11-113 6-OEt 2 Mor O11-114 4-NO₂ 2 NHMe O11-115 4-NO₂ 2 NMe₂ O11-116 4-NO₂ 2 Pip O11-117 4-NO₂ 2 Mor O11-118 4-NO₂ 2 NHMe S11-119 4-NO₂ 2 NMe₂ S11-120 4-NO₂ 2 Pip S11-121 4-NO₂ 2 Mor S11-122 5-NO₂ 2 NHMe O11-123 5-NO₂ 2 NMe₂ O11-124 5-NO₂ 2 Pip O11-125 5-NO₂ 2 Mor O11-126 5-NO₂ 2 NHMe S11-127 5-NO₂ 2 NMe₂ S11-128 5-NO₂ 2 Pip S11-129 5-NO₂ 2 Mor S11-130 6-NO₂ 2 NHMe O11-131 6-NO₂ 2 NMe₂ O11-132 6-NO₂ 2 Pip O11-133 6-NO₂ 2 Mor O11-134 4-NO₂The Pip O of 6-Cl 2 (table 12)Compound number (R¹)_m n R² _b X12-1 H 2 NHMe O12-2 H 2 NMe₂ O12-3 H 2 Pip O12-4 H 2 Mor O12-5 H 2 NHMe S12-6 H 2 NMe₂ S12-7 H 2 Pip S12-8 H 2 Mor S12-9 7-F 2 Pip O12-10 7-F 2 Mor O12-11 7-F 2 Pip S12-12 7-F 2 Mor S12-13 5-F 2 NHMe O12-14 5-F 2 NMe₂ O12-15 5-F 2 Pip O12-16 5-F 2 Mor O12-17 5-F 2 NHMe S12-18 5-F 2 NMe₂ S12-19 6-F 2 NHMe O12-20 6-F 2 NMe₂ O12-21 6-F 2 Pip O12-22 6-F 2 Mor O12-23 7-Cl 2 NHMe O12-24 7-Cl 2 NMe₂ O12-25 7-Cl 2 Pip O12-26 7-Cl 2 Mor O12-27 7-Cl 2 NHMe S12-28 7-Cl 2 NMe₂ S12-29 5-Cl 2 NHMe O12-30 5-Cl 2 NMe₂ O12-31 5-Cl 2 Pip O12-32 5-Cl 2 Mor O12-33 5-Cl 2 NHMe S12-34 5-Cl 2 NMe₂ S12-35 5-Cl 2 Pip S12-36 5-Cl 2 Mor S12-37 6-Cl 2 NHMe O12-38 6-Cl 2 NMe₂ O12-39 6-Cl 2 Pip O12-40 6-Cl 2 Mor O12-41 7-Cl 6-Cl 2 NHMe O12-42 7-Cl 6-Cl 2 NMe₂ O12-43 7-Cl 6-Cl 2 Pip O12-44 7-Br 2 Mor O12-45 5-Br 2 NHMe O12-46 5-Br 2 NMe₂ O12-47 5-Br 2 Pip O12-48 5-Br 2 Mor O12-49 5-Br 2 NHMe S12-50 5-Br 2 NMe₂ S12-51 6-Br 2 NHMe O12-52 6-Br 2 NMe₂ O12-53 6-Br 2 Pip O12-54 6-Br 2 Mor O12-55 7-Br 6-Cl 2 Pip O12-56 7-Me 2 NHMe O12-57 7-Me 2 NMe₂ O12-58 7-Me 2 Pip O12-59 7-Me 2 Mor O12-60 7-Me 2 NHMe S12-61 7-Me 2 NMe₂ S12-62 7-Me 2 Pip S12-63 7-Me 2 Mor S12-64 5-Me 2 NHMe O12-65 5-Me 2 NMe₂ O12-66 5-Me 2 Pip O12-67 5-Me 2 Mor O12-68 5-Me 2 NHMe S12-69 5-Me 2 NMe₂ S12-70 6-Me 2 NHMe O12-71 6-Me 2 NMe₂ O12-72 6-Me 2 Pip O12-73 6-Me 2 Mor O12-74 6-Me 7-Cl 2 Pip O12-75 7-Et 2 Pip O12-76 7-Et 2 Mor O12-77 5-Et 2 Pip O12-78 5-Et 2 Mor O12-79 5-Et 2 Pip S12-80 5-Et 2 Mor S12-81 6-Et 2 Pip O12-82 6-Et 2 Mor O12-83 6-Et 7-Cl 2 Mor O12-84 7-OMe 2 NHMe O12-85 7-OMe 2 NMe₂ O12-86 7-OMe 2 Pip O12-87 7-OMe 2 Mor O12-88 7-OMe 2 NHMe S12-89 7-OMe 2 NMe₂ S12-90 7-OMe 2 Pip S12-91 7-OMe 2 Mor S12-92 5-OMe 2 NHMe O12-93 5-OMe 2 NMe₂ O12-94 5-OMe 2 Pip O12-95 5-OMe 2 Mor O12-96 5-OMe 2 NHMe S12-97 5-OMe 2 NMe₂ S12-98 5-OMe 2 Pip S12-99 5-OMe 2 Mor S12-100 6-OMe 2 NHMe O12-101 6-OMe 2 NMe₂ O12-102 6-OMe 2 Pip O12-103 6-OMe 2 Mor O12-104 7-OEt 2 Pip O12-105 7-OEt 2 Mor O12-106 7-OEt 2 Pip S12-107 7-OEt 2 Mor S12-108 5-OEt 2 Pip O12-109 5-OEt 2 Mor O12-110 5-OEt 2 Pip S12-111 5-OEt 2 Mor S12-112 6-OEt 2 Pip O12-113 6-OEt 2 Mor O12-114 7-NO₂ 2 NHMe O12-115 7-NO₂ 2 NMe₂ O12-116 7-NO₂ 2 Pip O12-117 7-NO₂ 2 Mor O12-118 7-NO₂ 2 NHMe S12-119 7-NO₂ 2 NMe₂ S12-120 7-NO₂ 2 Pip S12-121 7-NO₂ 2 Mor S12-122 5-NO₂ 2 NHMe O12-123 5-NO₂ 2 NMe₂ O12-124 5-NO₂ 2 Pip O12-125 5-NO₂ 2 Mor O12-126 5-NO₂ 2 NHMe S12-127 5-NO₂ 2 NMe₂ S12-128 5-NO₂ 2 Pip S12-129 5-NO₂ 2 Mor S12-130 6-NO₂ 2 NHMe O12-131 6-NO₂ 2 NMe₂ O12-132 6-NO₂ 2 Pip O12-133 6-NO₂ 2 Mor O12-134 7-NO₂The Pip O of 6-Cl 2 (table 13)

Compound number (R¹)_m n R² _b X13-1 H 2 NHMe O13-2 H 2 NMe₂ O13-3 H 2 Pip O13-4 H 2 Mor O13-5 H 2 NHMe S13-6 H 2 NMe₂ S13-7 H 2 Pip S13-8 H 2 Mor S13-9 7-F 2 Pip O13-10 7-F 2 Mor O13-11 7-F 2 Pip S13-12 7-F 2 Mor S13-13 4-F 2 NHMe O13-14 4-F 2 NMe₂ O13-15 4-F 2 Pip O13-16 4-F 2 Mor O13-17 4-F 2 NHMe S13-18 4-F 2 NMe₂ S13-19 6-F 2 NHMe O13-20 6-F 2 NMe₂ O13-21 6-F 2 Pip O13-22 6-F 2 Mor O13-23 7-Cl 2 NHMe O13-24 7-Cl 2 NMe₂ O13-25 7-Cl 2 Pip O13-26 7-Cl 2 Mor O13-27 7-Cl 2 NHMe S13-28 7-Cl 2 NMe₂ S13-29 4-Cl 2 NHMe O13-30 4-Cl 2 NMe₂ O13-31 4-Cl 2 Pip O13-32 4-Cl 2 Mor O13-33 4-Cl 2 NHMe S13-34 4-Cl 2 NMe₂ S13-35 4-Cl 2 Pip S13-36 4-Cl 2 Mor S13-37 6-Cl 2 NHMe O13-38 6-Cl 2 NMe₂ O13-39 6-Cl 2 Pip O13-4O 6-Cl 2 Mor O13-41 7-Cl 6-Cl 2 NHMe O13-42 7-Cl 6-Cl 2 NMe₂ O13-43 7-Cl 6-Cl 2 Pip O13-44 7-Br 2 Mor O13-45 4-Br 2 NHMe O13-46 4-Br 2 NMe₂ O13-47 4-Br 2 Pip O13-48 4-Br 2 Mor O13-49 4-Br 2 NHMe S13-50 4-Br 2 NMe₂ S13-51 6-Br 2 NHMe O13-52 6-Br 2 NMe₂ O13-53 6-Br 2 Pip O13-54 6-Br 2 Mor O13-55 7-Br 6-Cl 2 Pip O13-56 7-Me 2 NHMe O13-57 7-Me 2 NMe₂ O13-58 7-Me 2 Pip O13-59 7-Me 2 Mor O13-60 7-Me 2 NHMe S13-61 7-Me 2 NMe₂ S13-62 7-Me 2 Pip S13-63 7-Me 2 Mor S13-64 4-Me 2 NHMe O13-65 4-Me 2 NMe₂ O13-66 4-Me 2 Pip O13-67 4-Me 2 Mor O13-68 4-Me 2 NHMe S13-69 4-Me 2 NMe₂ S13-70 6-Me 2 NHMe O13-71 6-Me 2 NMe₂ O13-72 6-Me 2 Pip O13-73 6-Me 2 Mor O13-74 6-Me 7-Cl 2 Pip O13-75 7-Et 2 PiP O13-76 7-Et 2 Mor O13-77 4-Et 2 Pip O13-78 4-Et 2 Mor O13-79 4-Et 2 Pip S13-80 4-Et 2 Mor S13-81 6-Et 2 Pip O13-82 6-Et 2 Mor O13-83 6-Et 7-C1 2 Mor O13-84 7-OMe 2 NHMe O13-85 7-OMe 2 NMe₂ O13-86 7-OMe 2 Pip O13-87 7-OMe 2 Mor O13-88 7-OMe 2 NHMe S13-89 7-OMe 2 NMe₂ S13-90 7-OMe 2 Pip S13-91 7-OMe 2 Mor S13-92 4-OMe 2 NHMe O13-93 4-OMe 2 NMe₂ O13-94 4-OMe 2 Pip O13-95 4-OMe 2 Mor O13-96 4-OMe 2 NHMe S13-97 4-OMe 2 NMe₂ S13-98 4-OMe 2 Pip S13-99 4-OMe 2 Mor S13-100 6-OMe 2 NHMe O13-101 6-OMe 2 NMe₂ O13-102 6-OMe 2 Pip O13-103 6-OMe 2 Mor O13-104 7-OEt 2 Pip O13-105 7-OEt 2 Mor O13-106 7-OEt 2 Pip S13-107 7-OEt 2 Mor S13-108 4-OEt 2 Pip O13-109 4-OEt 2 Mor O13-110 4-OEt 2 Pip S13-111 4-OEt 2 Mor S13-112 6-OEt 2 Pip O13-113 6-OEt 2 Mor O13-114 7-NO₂ 2 NHMe O13-115 7-NO₂ 2 NMe₂ O13-116 7-NO₂ 2 Pip O13-117 7-NO₂ 2 Mor O13-118 7-NO₂ 2 NHMe S13-119 7-NO₂ 2 NMe₂ S13-120 7-NO₂ 2 Pip S13-121 7-NO₂ 2 Mor S13-122 4-NO₂ 2 NHMe O13-123 4-NO₂ 2 NMe₂ O13-124 4-NO₂ 2 Pip O13-125 4-NO₂ 2 Mor O13-126 4-NO₂ 2 NHMe S13-127 4-NO₂ 2 NMe₂ S13-128 4-NO₂ 2 Pip S13-129 4-NO₂ 2 Mor S13-130 6-NO₂ 2 NHMe O13-131 6-NO₂ 2 NMe₂ O13-132 6-NO₂ 2 Pip O13-133 6-NO₂ 2 Mor O13-134 7-NO₂The Pip O of 6-Cl 2 (table 14)Compound number (R¹)_m n R² _b X14-1 H 2 NHMe O14-2 H 2 NMe₂ O14-3 H 2 Pip O14-4 H 2 Mor O14-5 H 2 NHMe S14-6 H 2 NMe₂ S14-7 H 2 Pip S14-8 H 2 Mor S14-9 7-F 2 Pip O14-10 7-F 2 Mor O14-11 7-F 2 Pip S14-12 7-F 2 Mor S14-13 4-F 2 NHMe O14-14 4-F 2 NMe₂ O14-15 4-F 2 Pip O14-16 4-F 2 Mor O14-17 4-F 2 NHMe S14-18 4-F 2 NMe₂ S14-19 5-F 2 NHMe O14-20 5-F 2 NMe₂ O14-21 5-F 2 Pip O14-22 5-F 2 Mor O14-23 7-Cl 2 NHMe O14-24 7-Cl 2 NMe₂ O14-25 7-Cl 2 Pip O14-26 7-Cl 2 Mor O14-27 7-Cl 2 NHMe S14-28 7-Cl 2 NMe₂ S14-29 4-Cl 2 NHMe O14-30 4-Cl 2 NMe₂ O14-31 4-Cl 2 Pip O14-32 4-Cl 2 Mor O14-33 4-Cl 2 NHMe S14-34 4-Cl 2 NMe₂ S14-35 4-Cl 2 Pip S14-36 4-Cl 2 Mor S14-37 5-Cl 2 NHMe O14-38 5-Cl 2 NMe₂ O14-39 5-Cl 2 Pip O14-40 5-Cl 2 Mor O14-41 7-Cl 5-Cl 2 NHMe O14-42 7-Cl 5-Cl 2 NMe₂ O14-43 7-Cl 5-Cl 2 Pip O14-44 7-Br 2 Mor O14-45 4-Br 2 NHMe O14-46 4-Br 2 NMe₂ O14-47 4-Br 2 Pip O14-48 4-Br 2 Mor O14-49 4-Br 2 NHMe S14-50 4-Br 2 NMe₂ S14-51 5-Br 2 NHMe O14-52 5-Br 2 NMe₂ O14-53 5-Br 2 Pip O14-54 5-Br 2 Mor O14-55 7-Br 5-Cl 2 Pip O14-56 7-Me 2 NHMe O14-57 7-Me 2 NMe₂ O14-58 7-Me 2 Pip O14-59 7-Me 2 Mor O14-60 7-Me 2 NHMe S14-61 7-Me 2 NMe₂ S14-62 7-Me 2 Pip S14-63 7-Me 2 Mor S14-64 4-Me 2 NHMe O14-65 4-Me 2 NMe₂ O14-66 4-Me 2 Pip O14-67 4-Me 2 Mor O14-68 4-Me 2 NHMe S14-69 4-Me 2 NMe₂ S14-70 5-Me 2 NHMe O14-71 5-Me 2 NMe₂ O14-72 5-Me 2 Pip O14-73 5-Me 2 Mor O14-74 5-Me 7-Cl 2 Pip O14-75 7-Et 2 Pip O14-76 7-Et 2 Mor O14-77 4-Et 2 Pip O14-78 4-Et 2 Mor O14-79 4-Et 2 Pip S14-80 4-Et 2 Mor S14-81 5-Et 2 Pip O14-82 5-Et 2 Mor O14-83 5-Et 7-Cl 2 Mor O14-84 7-OMe 2 NHMe O14-85 7-OMe 2 NMe₂ O14-86 7-OMe 2 Pip O14-87 7-OMe 2 Mor O14-88 7-OMe 2 NHMe S14-89 7-OMe 2 NMe₂ S14-90 7-OMe 2 PiP S14-91 7-OMe 2 Mor S14-92 4-OMe 2 NHMe O14-93 4-OMe 2 NMe₂ O14-94 4-OMe 2 Pip O14-95 4-OMe 2 Mor O14-96 4-OMe 2 NHMe S14-97 4-OMe 2 NMe₂ S14-98 4-OMe 2 Pip S14-99 4-OMe 2 Mor S14-100 5-OMe 2 NHMe O14-101 5-OMe 2 NMe₂ O14-102 5-OMe 2 Pip O14-103 5-OMe 2 Mor O14-104 7-OEt 2 Pip O14-105 7-OEt 2 Mor O14-106 7-OEt 2 Pip S14-107 7-OEt 2 Mor S14-108 4-OEt 2 Pip O14-109 4-OEt 2 Mor O14-110 4-OEt 2 Pip S14-111 4-OEt 2 Mor S14-112 5-OEt 2 Pip O14-113 5-OEt 2 Mor O14-114 7-NO₂ 2 NHMe O14-115 7-NO₂ 2 NMe₂ O14-116 7-NO₂ 2 Pip O14-117 7-NO₂ 2 Mor O14-118 7-NO₂ 2 NHMe S14-119 7-NO₂ 2 NMe₂ S14-120 7-NO₂ 2 Pip S14-121 7-NO₂ 2 Mor S14-122 4-NO₂ 2 NHMe O14-123 4-NO₂ 2 NMe₂ O14-124 4-NO₂ 2 Pip O14-125 4-NO₂ 2 Mor O14-126 4-NO₂ 2 NHMe S14-127 4-NO₂ 2 NMe₂ S14-128 4-NO₂ 2 Pip S14-129 4-NO₂ 2 Mor S14-130 5-NO₂ 2 NHMe O14-131 5-NO₂ 2 NMe₂ O14-132 5-NO₂ 2 Pip O14-133 5-NO₂ 2 Mor O14-134 7-NO₂The Pip O of 5-Cl 2 (table 15)

Compound number (R¹)_m n R² _b X15-1 H 2 NHMe O15-2 H 2 NMe₂ O15-3 H 2 Pip O15-4 H 2 Mor O15-5 H 2 NHMe S15-6 H 2 NMe₂ S15-7 H 2 Pip S15-8 H 2 Mor S15-9 5-F 2 NHMe O15-10 5-F 2 NMe₂ O15-11 5-F 2 Pip O15-12 5-F 2 Mor O15-13 6-F 2 NHMe O15-14 6-F 2 NMe₂ O15-15 6-F 2 Pip O15-16 6-F 2 Mor O15-17 6-F 2 NHMe S15-18 6-F 2 NMe₂ S15-19 6-F 2 Pip S15-20 6-F 2 Mor S15-21 5-Cl 2 NHMe O15-22 5-Cl 2 NMe₂ O15-23 5-Cl 2 Pip O15-24 5-Cl 2 Mor O15-25 6-Cl 2 NHMe O15-26 6-Cl 2 NMe₂ O15-27 6-Cl 2 Pip O15-28 6-Cl 2 Mor O15-29 6-Cl 2 NHMe S15-30 6-Cl 2 NMe₂ S15-31 6-Cl 2 Pip S15-32 6-Cl 2 Mor S15-33 5-Br 2 Mor O15-34 6-Br 2 NHMe O15-35 6-Br 2 NMe₃ O15-36 6-Br 2 Pip O15-37 6-Br 2 Mor O15-38 5-Me 2 NHMe O15-39 5-Me 2 NMe₂ O15-40 5-Me 2 Pip O15-41 5-Me 2 Mor O15-42 6-Me 2 NHMe O15-43 6-Me 2 NMe₂ O15-44 6-Me 2 Pip O15-45 6-Me 2 Mor O15-46 6-Me 2 NHMe S15-47 6-Me 2 NMe₂ S15-48 6-Me 2 Pip S15-49 6-Me 2 Mor S15-50 5-Et 2 Pip O15-51 5-Et 2 Mor O15-52 6-Et 2 Pip O15-53 6-Et 2 Mor O15-54 5-MeO 2 NHMe O15-55 5-MeO 2 NMe₂ O15-56 5-MeO 2 Pip O15-57 5-MeO 2 Mor O15-58 6-MeO 2 NHMe O15-59 6-MeO 2 NMe₂ O15-60 6-MeO 2 Pip O15-61 6-MeO 2 Mor O15-62 6-MeO 2 NHMe S15-63 6-MeO 2 NMe₂ S15-64 6-MeO 2 Pip S15-65 6-MeO 2 Mor S15-66 5-EtO 2 Pip O15-67 5-EtO 2 Mor O15-68 6-EtO 2 Pip O15-69 6-EtO 2 Mor O15-70 5-NO₂ 2 NHMe O15-71 5-NO₂ 2 NMe₂ O15-72 5-NO₂ 2 Pip O15-73 5-NO₂ 2 Mor O15-74 6-NO₂ 2 NHMe O15-75 6-NO₂ 2 NMe₂ O15-76 6-NO₂ 2 Pip O15-77 6-NO₂ 2 Mor O15-78 6-NO₂ 2 NHMe S15-79 6-NO₂ 2 NMe₂ S15-80 6-NO₂ 2 Pip S15-81 6-NO₂2 Mor S (table 16)

Compound number (R¹)_m n R² _b X16-1 H 2 NHMe O16-2 H 2 NMe₂ O16-3 H 2 Pip O16-4 H 2 Mor O16-5 H 2 NHMe S16-6 H 2 NMe₂ S16-7 H 2 Pip S16-8 H 2 Mor S16-9 4-F 2 Pip O16-10 4-F 2 Mor O16-11 4-F 2 Pip S16-12 4-F 2 Mor S16-13 5-F 2 NHMe O16-14 5-F 2 NMe₂ O16-15 5-F 2 Pip O16-16 5-F 2 Mor O16-17 4-Cl 2 NHMe O16-18 4-Cl 2 NMe₂ O16-19 4-Cl 2 Pip O16-20 4-Cl 2 Mor O16-21 4-Cl 2 NHMe S16-22 4-Cl 2 NMe₂ S16-23 4-Cl 2 Pip S16-24 4-Cl 2 Mor S16-25 5-Cl 2 NHMe O16-26 5-Cl 2 NMe₂ O16-27 5-Cl 2 Pip O16-28 5-Cl 2 Mor O16-29 4-Br 2 NHMe O16-30 4-Br 2 NMe₂ O16-31 4-Br 2 Pip O16-32 5-Br 2 Mor O16-33 4-Me 2 NHMe O16-34 4-Me 2 NMe₂ O16-35 4-Me 2 Pip O16-36 4-Me 2 Mor O16-37 4-Me 2 NMHe S16-38 4-Me 2 NMe₂ S16-39 4-Me 2 Pip S16-40 4-Me 2 Mor S16-41 5-Me 2 NHMe O16-42 5-Me 2 NMe₂ O16-43 5-Me 2 Pip O16-44 5-Me 2 Mor O16-45 4-Et 2 Pip O16-46 4-Et 2 Mor O16-47 5-Et 2 Pip O16-48 5-Et 2 Mor O16-49 4-MeO 2 NHMe O16-50 4-MeO 2 NMe₂ O16-51 4-MeO 2 Pip O16-52 4-MeO 2 Mor O16-53 4-MeO 2 NHMe S16-54 4-MeO 2 NMe₂ S16-55 4-MeO 2 Pip S16-56 4-MeO 2 Mor S16-57 5-MeO 2 NHMe O16-58 5-MeO 2 NMe₂ O16-59 5-MeO 2 Pip O16-60 5-MeO 2 Mor O16-61 4-EtO 2 Pip O16-62 4-EtO 2 Mor O16-63 5-EtO 2 Pip O16-64 5-EtO 2 Mor O16-65 4-NO₂ 2 NHMe O16-66 4-NO₂ 2 NMe₂ O16-67 4-NO₂ 2 Pip O16-68 4-NO₂ 2 Mor O16-69 4-NO₂ 2 NHMe S16-70 4-NO₂ 2 NMe₂ S16-71 4-NO₂ 2 Pip S16-72 4-NO₂ 2 Mor S16-73 5-NO₂ 2 NHMe O16-74 5-NO₂ 2 NMe₂ O16-75 5-NO₂ 2 Pip O16-76 5-NO₂ 2 Mor O

What follows compound can be provided and lead to formula (I) isoxazole derivatives [formula (Ia), (Ib), (Ic), (Id) and (Ie)] as the suitable present invention：1-3,1-13,1-15,1-19,1-22,1-25,1-28,1-31,1-38,1-41,1-44,1-47,1-

48,1-49,1-50,1-51,1-53,1-56,1-59,1-60,1-62,1-66,1-68,1-69,1-721-75,1-76,

1-85,1-96,1-97,1-98,1-107,1-119,1-122,1-125,1-126,1-128,1-135,1-142,1-148,

1-151,1-160,1-168,1-169,1-170,1-173,1-176,1-185,1-186,1-191,1-193,1-197,1-

198,1-199,1-200,1-204,1-207,1-216,1-217,1-218,1-219,1-220,1-221,1-224,1-

231,1-240,1-241,1-242,1-243,1-244,1-247,1-263,1-264,1-265,1-266,1-267,1-

268,1-269,1-272,1-275,1-277,1-278,1-281,1-283,1-284,1-285,1-286,1-287,1-

291,1-292,1-293,1-294,1-310,1-311,1-312,1-328,1-346,1-362,1-363,1-364,1-

365,1-381,1-384,1-400,1-401,1-402,1-403,1-404,1-405,1-406,1-414,1-421,1-

422,1-423,1-429,1-435,1-438,1-439,1-440,1-441,1-442,1-448,1-457,1-460,1-

461,1-462,1-463,1-464,1-465,1-471,1-473,1-474,1-480,1-481,1-482,1-490,1-

497,1-498,1-499,1-500,1-501,1-502,1-518,1-519,1-520,1-521,1-528,1-534,1-537,1-

550,1-553,1-554,1-555,1-556,1-572,1-573,1-574,1-575,1-576,1-577,1-578,1-

579,1-580,1-581,1-582,1-583,1-586,1-594,1-596,1-598,1-618,2-3,2-53,3-2,3-

3,3-18,3-19,3-41,3-83,4-2,4-3,5-2,5-3,6-2 or 6-3

Compound 1-3,1-13,1-15,1-22,1- shown in more preferably following sequence number

28,1-31,1-38,1-44,1-51,1-53,1-59,1-60,1-62,1-68,1-69,1-75,1-76,1-85,1-97,

1-98,1-107,1-119,1-126,1-128,1-142,1-148,1-151,1-160,1-169,1-170,1-173,1-

176,1-191,1-193,1-197,1-200,1-207,1-224,1-247,1-269,1-275,1-277,1-293,1-

294,1-312,1-328,1-346,1-365,1-384,1-405,1-406,1-414,1-422,1441,1-464,1-

473,1-480,1-481,1-482,1-490,1-498,1-502,1-521,1-537,1-556,1-572,1-574,1-

580,1-581,1-583,1-586,1-594,1-596,1-598,1-618,2-3,3-2,3-18,3-19,3-41,3-83

Or 4-2

Particularly preferably following compounds：Compound 1-3：3- (2- amino ethoxies) -1,2- benzoisoxazoles, compound 1-15：Fluoro- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -5-, compound 1-22：The fluoro- 4- methyl isophthalic acids of 3- (2- amino ethoxies) -5-, 2- benzoisoxazoles, compound 1-31：Fluoro- 1, the 2- benzoisoxazoles of 3- (2- aminoethanethios) -5-, compound 1-53：Chloro- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -5-, compound 1-59：Chloro- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -5,7- bis-, compound 1-62：The chloro- 7- methyl isophthalic acids of 3- (2- aminoethanethios) -5-, 2- benzoisoxazoles, compound 1-69：Chloro- 1, the 2- benzoisoxazoles of 3- (2- aminoethanethios) -5-, compound 1-85：Chloro- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -6-, compound 1-97：Chloro- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -7-, compound 1-119：Bromo- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -5-, compound 1-142：3- (2- amino ethoxies) -5- methyl isophthalic acids, 2- benzoisoxazoles, compound 1-151：3- (2- aminoethanethios) -5- methyl isophthalic acids, 2- benzoisoxazoles, compound 1-160：3- (2- amino ethoxies) -6- methyl isophthalic acids, 2- benzoisoxazoles, compound 1-169：3- (2- amino ethoxies) -7- methyl isophthalic acids, 2- benzoisoxazoles, compound 1-193：3- (2- amino ethoxies) -5- methoxyl group -1,2- benzoisoxazoles, compound 1-197：3- (2- aminoethanethios) -5- methoxyl group -1,2- benzoisoxazoles, compound 1-224：3- (2- amino ethoxies) -5- difluoro-methoxy -1,2- benzoisoxazoles, compound 1-269：Fluoro- 4- methyl mercaptos -1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -5-, compound 1-422：3- (2- amino ethoxies) -5- methoxycarbonyl group -1,2- benzoisoxazoles, compound 1-521：3- (2- amino ethoxies) -5- nitro -1,2- benzoisoxazoles, compound 1-537：3- (2- aminoethanethios) -5- nitro -1,2- benzoisoxazoles, compound 1-572：3- (2- amino ethoxies) -4- cyano group -1,2- benzoisoxazoles, or compound 3-2：3- (2- amino ethoxies) pyrido [3,2-d] isoxazoles.

What follows compound can be provided and lead to isoxazole derivatives [formula (Ia), (Ib), (Ic), (Id), (Ie), (IIa), (IIb), (IIc), (IId) or (IIe)] shown in formula (II) as the suitable present invention as MAOI active component of the present invention：1-3,1-13,1-15,1-19,1-22,1-25,1-28,1-31,1-38,1-41,1-44,1-47,1-48,1-49,1-50,1-51,1-53,1-56,1-59,1-60,1-62,1-66,1-68,1-69,1-72,1-75,1-76,1-85,1-96,1-97,1-98,1-107,1-119,1-122,1-125,1-126,1-128,1-135,1-142,1-148,1-151,1-160,1-168,1-169,1-170,1-173,1-176,1-185,1-186,1-191,1-193,1-197,1-198,1-199,1-200,1-204,1-207,1-216,1-217,1-218,1-219,1-220,1-221,1-224,1-231,1-240,1-241,1-242,1-243,1-244,1-247,1-263,1-264,1-265,1-266,1-267,1-268,1-269,1-272,1-275,1-277,1-278,1-281,1-283,1-284,1-285,1-286,1-287,1-291,1-292,1-293,1-294,1-310,1-311,1-312,1-328,1-346,1-362,1-363,1-364,1-365,1-381,1-384,1-400,1-401,1-402,1-403,1-404,1-405,1-406,1-414,1-421,1-422,1-423,1-429,1-435,1-438,1-439,1-440,1-441,1-442,1-448,1-457,1-460,1-461,1-462,1-463,1-464,1-465,1-471,1-473,1-474,1-480,1-481,1-482,1-490,1-497,1-498,1-499,1-500,1-501,1-502,1-518,1-519,1-520,1-521,1-528,1-534,1-537,1-550,1-553,1-554,1-555,1-556,1-572,1-573,1-574,1-575,1-576,1-577,1-578,1-579,1-580,1-581,1-582,1-583,1-586,1-594,1-596,1-598,1-618,2-3,2-53,3-2,3-3,3-18,3-19,4-2,4-3,5-2,5-3,6-2,6-3,9-1,9-2,9-5,9-6,10-1,10-2,10-5,10-6,1 1-1,1 1-2,1 1-5,1 1-6,12-1,12-2,12-5,12-6,13-1,13-2,13-5,13-6,14-1,14-2,14-5,14-6,15-1,15-2,15-5,15-6,16-1,16-2,16-5 or 16-6.

Compound 1-3 shown in more preferably following sequence number, 1-13, 1-15, 1-22, 1-28, 1-31, 1-44, 1-51, 1-53, 1-59, 1-60, 1-62, 1-68, 1-69, 1-75, 1-76, 1-85, 1-97, 1-98, 1-107, 1-119, 1-126, 1-128, 1-142, 1-148, 1-151, 1-160, 1-169, 1-170, 1-173, 1-176, 1-191, 1-193, 1-197, 1-200, 1-207, 1-224, 1-247, 1-269, 1-275, 1-277, 1-293, 1-294, 1-312, 1-328, 1-346, 1-365, 1-384, 1-405, 1406, 1-414, 1422, 1-441, 1464, 1473, 1-480, 1-481, 1-482, 1490, 1498, 1-502, 1-521, 1-537, 1-556, 1-572, 1-574, 1-580, 1-581, 1-583, 1-586, 1-594, 1-596, 1-598, 1-618, 2-3, 3-2, 3-18, 3-19, 3-41, 3-83 or 4-2.

The synthetic method of the compounds of this invention is as follows.(method A)(method B)(method C)

(method D)(method E)(method F)

(method G)

In above formula, R¹、R², m, n, ring A and X be as described above, work as R¹ _aRepresent C₁-C₆Alkyl, C₁-C₆Alkylthio group, C₁-C₆Alkoxy carbonyl group, carboxyl, dithiocarboxyl or (C₁-C₆Alkylthio group) thiocarbonyl group when, R¹ _bRepresent C₁-C₆Alkyl, R³Represent ester residue, R³ _aRepresent C₁-C₄Alkyl, R⁴Protected amino is represented, Y represents hydroxyl or leaving group, and Z represents the integer of halogen atom and m ' expressions 1 or 2.

R¹ _aDescribed in C₁-C₆Alkyl or C₁-C₆C in alkylthio radicals₁-C₆Moieties are as described above；R¹ _aIt can be such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, 2- methyl butyls, neopentyl, 1- ethyl propyls, hexyl, 4- methyl amyls, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 3,3- dimethylbutyls, 2,2- dimethylbutyls, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 1,3- dimethylbutyl, 2,3- dimethylbutyls, 2- ethyl-butyls, methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, butylthio, isobutylthio, secondary butylthio, tertiary butylthio, penta sulfenyl, isopentylthio, 2- methylbutylthios, new penta sulfenyl, 1- ethyl rosickyite bases, own sulfenyl, 4- methyl penta sulfenyls, 3- methyl penta sulfenyls, 2- methyl penta sulfenyls, 1- methyl penta sulfenyls, 3,3- dimethyl butyrate sulfenyls, 2,2- dimethyl butyrate sulfenyls, 1,1- dimethyl butyrate sulfenyl, 1,2- dimethyl butyrate sulfenyl, 1,3- dimethyl butyrate sulfenyl, 2,3- dimethyl butyrate sulfenyls, 2- ethyl butylthios, methoxycarbonyl group, carbethoxyl group, propylene carbonyl oxygen, butyloxycarbonyl, butoxy carbonyl, isobutyl boc, secondary butoxy carbonyl, tertbutyloxycarbonyl, penta oxygen carbonyl, own oxygen carbonyl, carboxyl, dithiocarboxyl or (methyl mercapto) thiocarbonyl group, preferably C₁-C₄Alkyl, C₁-C₄Alkylthio group, C₁-C₄Alkoxy carbonyl group, carboxyl or dithiocarboxyl group, and more preferably methyl, ethyl, methyl mercapto, ethylmercapto group or carboxyl.

R¹ _bDescribed in C₁-C₆Alkyl is as described above and can be such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, 2- methyl butyls, neopentyl, 1- ethyl propyls, hexyl, 4- methyl amyls, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 3,3- dimethyl amyl groups, 2,2- dimethyl amyl groups, 1,1- dimethyl amyl groups, 1,2- dimethyl amyl groups, 1,3- dimethyl amyl groups, 2,3- dimethyl amyl groups or 2- ethyl-butyl groups, preferably C₁-C₄Alkyl group, and more preferably methyl or ethyl.

R³Described in ester residue can be such as C₁-C₆Alkyl group such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group or hexyl；The either C of substitution₁-C₄(substituent can be halogen atom, C to alkyl group₁-C₄Alkoxy, halogen-or C₁-C₄The C of alkoxy-substituted₁-C₄Alkoxy base, C₆-C₁₄Aryl is selected from C by 1-3₁-C₄Alkyl, C₁-C₄Alkoxy, nitro, the C of the substituent group of halogen and cyano group₆-C₁₄Aryl) such as 2- fluoro ethyls, 2- chloroethyls, 2- bromoethyls, 2,2- dibromoethyls, 2,2,2- trichloroethyls, 3- fluoropropyls, 4- chlorobutyls, methoxy, 1,1- dimethyl -1- methoxies, ethoxyl methyl, n-propoxymethyl, i-propoxymethyl, n-butoxy methyl, t-butoxymethyl, 1- ethoxyethyl groups, 1- methyl isophthalic acids-methoxy ethyl, 1- (isopropoxy) ethyl, 3- methoxy-propyl -4- methoxybutyls, fluorine methoxy, 2,2,2- tri-chloroethoxy ylmethyls, two (2- chloroethoxies) methyl, 3- fluorine propoxy methyls, 4- chlorine butoxyethyl groups, dibromo methoxy ethyl, 2- chloroethoxy propyl group, fluorine methoxybutoxy, 2- methoxvethoxvmethvls, ethyoxyl methoxy ethyl, methoxyethoxypropyl, methoxy ethoxy butyl, benzyl, phenethyl, 3- phenyl propyls, 4- phenyl butyls, Alpha-Naphthyl methyl, betanaphthyl methyl, benzhydryl, trityl, Alpha-Naphthyl diphenyl methyl, 9- anthrylmethyls, 4- methyl-benzyls, 2,4,6- trimethyl benzyls, 3,4,5- trimethyl benzyls, 4- methoxy-benzyls, 4- methyoxyphenyldiphenylmethyl bases, 2- nitrobenzyls, 4- nitrobenzyls, 4- chlorobenzyls, 4- bromobenzyls, 4- cyanobenzyls, 4- cyanobenzyls diphenyl methyls, two (2- nitrobenzophenones) methyl or piperonyl group, preferably C₁-C₄Alkyl, 2- fluoro ethyls, 2- chloroethyls, 2- bromoethyls, 2, 2, 2- trichloroethyls, methoxy, ethoxyl methyl, fluorine methoxy, 2, 2, 2- tri-chloroethoxy ylmethyls, two (2- chloroethoxies) methyl, benzyl, phenethyl, 4- methyl-benzyls, 2, 4, 6- trimethyl benzyls, 4- methoxy-benzyls, 4- nitrobenzyls, 4- chlorobenzyls or 4- cyanobenzyls groups, and more preferably methyl, ethyl, 2, 2, 2- trichloroethyls, methoxy, ethoxyl methyl, fluorine methoxy, 2, 2, 2- tri-chloroethoxy ylmethyls, benzyl, phenethyl, 4- methyl-benzyls, 4- methoxy-benzyls, 4- nitrobenzyls, 4- chlorobenzyls or 4- cyanobenzyls groups.Particularly preferably methyl or ethyl.

R³ _aDescribed in C₁-C₄Alkyl can be such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group, preferably methyl or ethyl, and more preferably methyl.

R⁴Described in the protection group of protected amino group do not have the specific any group for limiting and amino group protection being typically used for, can be such as C₁-C₆Alkanoyl such as formoxyl, acetyl group, propiono, bytyry, isobutyryl, valeryl, valeryl, valeryl, isovaleryl or caproyl group；Halogen-or C₁-C₄The C of alkoxy-substituted₁-C₄Alkanoyl such as chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, 3- fluorine propiono, the chlorobutyryls of 4,4- bis-, Methoxyacetyl, butyl acetyl group, ethoxy-c acyl group or propoxyl group bytyry group；Undersaturated C₁-C₄Alkanoyl such as acryloyl group, propine acyl group, methacrylyl (methacryloyl), crotonyl or methacrylyl (isocrotonoyl) group；Can be by halogen, C₁-C₄Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkoxy carbonyl group, C₆-C₁₀Aryl or the C of nitro substitution₆-C₁₀Arylcarbonyl group such as benzoyl, α-naphthoyl, β-naphthoyl, 2- fluoro benzoyls, 2- benzoyl bromides, 2, 4- dichloro-benzoyl bases, chloro- α-the naphthoyls of 6-, 4- toluyl groups, 4- propylbenzoyls, 4- tert-butyl-benzoyls, 2, 4, 6- trimethylbenzoyls, 6- ethyls-α-naphthoyl, 4- anisoyl bases, 4- propoxyl group benzoyls, 4- tert-butoxy benzoyls, 6- ethyoxyls-α-naphthoyl, 2- carbethoxyl group benzoyls, 4- tertbutyloxycarbonyl benzoyls, 6- methoxycarbonyl groups-α-naphthoyl, 4- Phenylbenzoyls, 4- phenyl-α-naphthoyl, 6- Alpha-Naphthyl benzoyls, 4- nitro benzoyls, 2- nitro benzoyls or 6- nitros-α-naphthoyl group；Can be by halogen or three C₁-C₄The C of aIkylsilyl groups substitution₁-C₄Alkoxycarbonyl group such as methoxycarbonyl group, carbethoxyl group, propylene carbonyl oxygen, isobutyl boc, butoxy carbonyl, isobutyl boc, secondary butoxy carbonyl, tertbutyloxycarbonyl, chloromethane oxygen carbonyl, 2,2,2- trichloro-ethoxycarbonyls, 2- fluorine propylene carbonyl oxygen, the bromo- tertbutyloxycarbonyls of 2-, the bromo- tertbutyloxycarbonyls of 2,2- bis-, triethylsilyl methoxycarbonyl group, 2- trimethyl silyls carbethoxyl group, 4- tripropylsilyl base butoxy carbonyls or t-butyldimethylsilyl propylene carbonyl oxygen group；C₂-C₅Chain ene keto carbonyl group such as vinyloxycarbonyl, allyloxycarbonyl, 1,3-butadiene oxygen carbonyl or 2- amylene oxygen carbonyl groups；Aryl dicarbapentaborane group such as phthalyl；Aromatic alkyl group such as benzyl, phenethyl, 3- phenyl propyls, 4- phenyl butyls, Alpha-Naphthyl methyl, betanaphthyl methyl, benzhydryl, trityl, Alpha-Naphthyl diphenyl methyl or 9- anthrylmethyl groups；Or the C that can be replaced by methoxyl group or nitro₇-C₁₅Arylalkyloxycarbonyl group such as benzyloxycarbonyl group, (1- phenyl) benzyloxycarbonyl group, Alpha-Naphthyl methoxycarbonyl group, betanaphthyl methoxycarbonyl group, 9- anthryls methoxycarbonyl group, p- methbxybenzyl-oxycarbonyl or p- nitrobenzyloxycarbonyl group, preferably C₁-C₄Alkanoyl, trifluoroacetyl group, Methoxyacetyl, benzoyl, α-naphthoyl, β-naphthoyl, anisoyl base, nitro benzoyl, C₁-C₄Alkoxy carbonyl group, methoxycarbonyl group, carbethoxyl group, tertbutyloxycarbonyl, 2; 2; 2- trichloro-ethoxycarbonyls, triethylsilyl methoxycarbonyl group, 2- trimethyl silyls carbethoxyl group, vinyloxycarbonyl, allyloxycarbonyl, phthalyl, benzyl, benzyloxycarbonyl group or nitrobenzyloxycarbonyl group, and more preferably formoxyl, acetyl group, benzoyl, 4- anisoyls base, 4- nitro benzoyls, methoxycarbonyl group, carbethoxyl group, butoxy carbonyl, tertbutyloxycarbonyl, phthalyl, benzyl, benzyloxycarbonyl group or p- nitrobenzyloxycarbonyl group.Particularly preferably tertbutyloxycarbonyl.

Leaving group does not have concrete restriction described in Y, as long as it usually can remove in nucleophilic residues form and can be such as halogen atom such as fluorine, chlorine, bromine or iodine atom；C₁-C₄Alkane sulfonyloxy group such as mesyloxy, ethanesulfonyloxy group, the third sulfonyloxy or fourth sulfonyloxy group；Halo C₁-C₄Alkane sulfonyloxy group such as trifluoro-methanesulfonyl oxy, 2,2,2- trichlorine ethanesulfonyloxy groups, 3,3,3- the third sulfonyloxies of tribromo or 4,4,4- trifluoro fourth sulfonyloxy groups；Or 1-3 C can be contained₁-C₄The C of alkyl₆-C₁₀Arylsulfonyloxy group such as phenylsulfonyloxy, α-naphthalene sulfonyl epoxide, β-naphthalene sulfonyl epoxide, tolysulfonyl epoxide, 4- tert-butyl benzenes sulfonyloxy, 2,4,6- front three phenylsulfonyloxies or 6- ethyls-α-naphthalene sulfonyl epoxide group.It is preferred that chlorine, bromine, iodine atom；Mesyloxy, ethanesulfonyloxy group, trifluoro-methanesulfonyl oxy, 2,2,2- trichlorine ethanesulfonyloxy groups；Phenylsulfonyloxy, tosyloxy or 2,4,6- trimethylbenzene sulfonyloxy groups, and more preferably chlorine, bromine, iodine atom；Mesyloxy, trifluoro-methanesulfonyl oxy, phenylsulfonyloxy, tolysulfonyl epoxide or 2,4,6- front three phenylsulfonyloxies.

Halogen atom described in Z can be such as fluorine, chlorine, bromine or iodine atom, and preferably fluorine or chlorine atom.

Starting compound (XIII) of the present invention or (XIX) are known compounds or [such as Chem.Abstr., 49,11594 (1955) can be synthesized by known method, Tetrahedron, 38,1457 (1982), Japan Patent Kokai Hei3-294267, Synth.Commun., 9,731 (1979), J.Org.Chem., 44,3292 (1979) or Chem.Ber., 100,954 (1967)].

Formula (XVII) compound can be known compound or can be synthesized by known method [such as Synthesis, 366 (1990), or J.Med.Chem., 34,1258 (1991)].

Its middle ring A can be known compound or [such as J.Med.Chem. can be synthesized by known method for formula (XV) compound of pyridyl ring, 32,2116 (1989) or J.Chem.Soc. (C), 172 (1968)].

Method A is the compound (I) synthetic method.

In step A1, in the presence of a base, handle formula (XIII) compound formula (XIV) compound is made with azanol in atent solvent.

Solvent for use does not have specific restriction, as long as it does not disturb described react simultaneously can dissolve a certain amount of raw material, it can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Alcohol such as methanol, ethanol, propyl alcohol, isopropanol, butanol or isobutanol；Acid amides such as formamide, dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide；Sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone；The aqueous mixture of water or above-mentioned organic solvent.It is preferred that ethers, alcohols, amide-type, the aqueous mixture of sulfoxide type or these organic solvents, and more preferably alcohol (particularly methanol or ethanol) or aqueous alcohol (particularly aqueous methanol or hydrous ethanol).

Alkali used can be such as alkali carbonate such as sodium carbonate, potassium carbonate or lithium carbonate；Alkali metal hydrogencarbonate such as sodium acid carbonate, saleratus or lithium bicarbonate；Alkali metal hydride such as sodium hydride, hydrofining or lithium hydride；Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide；Alkali metal alkane alkoxide such as sodium methoxide, caustic alcohol, potassium tert-butoxide or lithium methoxide；Alkali metal mercaptide such as sodium methyl mercaptide or ethyl mercaptan sodium；Organic amine such as triethylamine, tri-butylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4- (N, N- dimethylamino) pyridine, DMA, N, N- diethylanilines, 1,5- diazabicyclos [4,3,0] nonyl- 5- alkene, 1,4- diazabicyclos [2,2,2] octane (DABCO) or 1,8- diazabicyclo [5,4,0] 11-7- alkene (DBU)；Lithium alkylide such as lithium methide, ethyl-lithium or butyl lithium；Alkyl lithamide such as lithium diisopropylamide or lithium dicyclohexylamide.Preferred alkali metal carbonate, alkali metal hydroxide or alkali metal alkane alkoxide, and more preferably alkali metal hydroxide (particularly sodium hydroxide or potassium hydroxide).

The reaction temperature can change according to the raw material and reagent, but generally in the range of -10~100 DEG C and preferably in the range of 0~50 DEG C.

The reaction time can change according to the raw material, reagent or reaction temperature, but generally in the range of 10 minutes to 10 hours and preferably in the range of 30 minutes to 5 hours.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example after the completion of reacting, evaporation of solvent adds water so that water layer is acidified, and filters the compound being settled out into the residue.Or water is added into the reactant mixture and adds hydrophobic solvent (such as benzene, ether, ethyl acetate) to extract the purpose compound.The organic layer is washed with water, and anhydrous magnesium sulfate is dried and evaporates solvent, obtains the purpose compound.If desired, can for example be recrystallized with conventional method, gained purpose compound is purified or is converted into salt by adding acid by reprecipitation, chromatography.

In step A2, formula (XV) compound can be according to Chem.Ber., and the reaction described in 100,954 (1967) is made by formula (XIV) by the following method.(1) in atent solvent, reacted with thionyl chloride, phosgene or their equivalent (such as surpalite), then (2) react in atent solvent with alkali.

Solvent for use does not have specific restriction in step (1) and (2), as long as they disturbing reaction and can not dissolve a certain amount of raw material.They can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Or sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone.It is preferred that halogenated hydrocarbon (particularly dichloromethane, chloroform, carbon tetrachloride or dichloroethanes) or ethers (particularly ether, Di Iso Propyl Ether, tetrahydrofuran Huo dioxanes), and more preferably ethers (particularly ether, Di Iso Propyl Ether, tetrahydrofuran Huo dioxanes).

Alkali used can be such as alkali carbonate such as sodium carbonate, potassium carbonate or lithium carbonate in step (2)；Alkali metal hydrogencarbonate such as sodium acid carbonate, saleratus or lithium bicarbonate；Alkali metal hydride such as lithium hydride, sodium hydride or hydrofining；Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide；Alkali metal alkane alkoxide such as sodium methoxide, caustic alcohol, potassium tert-butoxide or lithium methoxide；Alkali metal mercaptide such as sodium methyl mercaptide or ethyl mercaptan sodium；Organic amine such as triethylamine, tri-butylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4- (N, N- dimethylamino) pyridine, DMA, N, N- diethylanilines, 1,5- diazabicyclos [4,3,0] nonyl- 5- alkene, 1,4- diazabicyclos [2,2,2] octane (DABCO) or 1,8- diazabicyclo [5,4,0] 11-7- alkene (DBU)；Lithium alkylide such as lithium methide or butyl lithium；Or alkyl lithamide such as lithium diisopropylamide or lithium dicyclohexylamide.It is preferred that organic amine, and more preferably triethylamine, tri-butylamine, diisopropyl ethyl amine, pyridine, 1,5- diazabicyclos [4,3,0] nonyl- 5- alkene, 1,4- diazabicyclos [2,2,2] octane (DABCO) or 1,8- diazabicyclo [5,4,0] 11-7- alkene (DBU).Particularly preferably triethylamine.

The reaction temperature of the step (1) and (2) can change according to the raw material or reagent, but generally in the range of -10~100 DEG C and preferably in the range of 0~50 DEG C.

The reaction time of the step (1) and (2) can change according to the raw material, reagent or reaction temperature, but generally in the range of 10 minutes to 10 hours and preferably in the range of 15 minutes to 5 hours.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example by the way that solvent is evaporated off, water is added into the reactant mixture, water layer is acidified, filter the product being settled out；Or by adding hydrophobic solvent (such as benzene, ether, ethyl acetate), extract is washed with water, it is dried with anhydrous magnesium sulfate and solvent is evaporated off, the purpose compound is isolated.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

In step A3, in atent solvent or without under solvent, the compound (XV) is reacted with halogenating agent, synthesize the compound (XVI) in the presence of with and without alkali (preferably in the presence of a base).

The halogenating agent can be such as phosphoryl chloride phosphorus oxychloride, phosphorus oxybromide, triiodo phosphorous oxide or phosphorus pentachloride, and preferably phosphoryl chloride phosphorus oxychloride, phosphorus pentachloride or their mixture.

Solvent for use does not have specific restriction, as long as they disturbing reaction and can not dissolve a certain amount of raw material, they can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Or sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone, it is preferred that halogenated hydrocarbon (particularly dichloromethane) or ethers (particularly tetrahydrofuran Huo dioxanes), and more preferably ethers (particularly ether, Di Iso Propyl Ether, tetrahydrofuran Huo dioxanes).

Alkali used can be such as alkali carbonate such as sodium carbonate, potassium carbonate or lithium carbonate；Alkali metal hydrogencarbonate such as sodium acid carbonate, saleratus or lithium bicarbonate；Alkali metal hydride such as lithium hydride, sodium hydride or hydrofining；Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide；Or organic amine such as triethylamine, tri-butylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4- (N, N- dimethylaminos) pyridine, N, accelerine, N, N- diethylanilines, 1,5- diazabicyclos [4,3,0] nonyl- 5- alkene, Isosorbide-5-Nitrae-diazabicyclo [2,2,2] octane (DABCO) or 1, -7- the alkene (DBU) of 8- diazabicyclos [5,4,0] 11, preferred alkali metal carbonate or organic amine, and more preferably organic amine (particularly triethylamine or pyridine).

The reaction temperature can change according to the raw material or reagent, but generally in the range of 0~150 DEG C and preferably in the range of 10~100 DEG C.

The reaction time can change according to the raw material, reagent or reaction temperature, but generally in the range of 30 minutes to 10 hours and preferably in the range of 1 to 5 hour.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example by the way that solvent is evaporated off, water is added into the reactant mixture, hydrophobic solvent (such as benzene, ether, ethyl acetate) is subsequently added, to extract the compound, organic layer is washed with water, and is dried with anhydrous magnesium sulfate and solvent is evaporated off, and isolates the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

In step 4, in the presence of a base, in atent solvent, the compound (XVI) is reacted with the formula (XVII) compound, the compound (XVIII) is synthesized.

Solvent for use does not have specific restriction, as long as they disturbing reaction and can not dissolve a certain amount of raw material, they can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Or acid amides such as formamide, dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide；Or sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone.It is preferred that ether, acid amides or sulfoxide, and more preferably ether (particularly ether, tetrahydrofuran Huo dioxanes) or acid amides (particularly dimethylformamide).

Alkali used can be such as alkali carbonate such as sodium carbonate, potassium carbonate or lithium carbonate；Alkali metal hydrogencarbonate such as sodium acid carbonate, saleratus or lithium bicarbonate；Alkali metal hydride such as lithium hydride, sodium hydride or hydrofining；Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide；Or organic amine such as triethylamine, tri-butylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4- (N, N- dimethylamino) pyridine, DMA, N, N- diethylanilines, 1,5- diazabicyclos [4,3,0] nonyl- 5- alkene, 1,4- diazabicyclos [2,2,2] octane (DABCO) or 1,8- diazabicyclo [5,4,0] 11-7- alkene (DBU)；Lithium alkylide such as lithium methide, ethyl-lithium or butyl lithium；Alkyl lithamide such as lithium diisopropylamide or lithium dicyclohexylamide, preferred alkali metal carbonate, alkali metal hydride or organic amine, and more preferably alkali carbonate (particularly sodium carbonate or potassium carbonate) or alkali metal hydride (particularly sodium hydride).

In order to accelerate reaction, crown ether such as dibenzo-18 crown-6 can be added.

The reaction temperature can change according to the raw material or reagent, but generally in the range of -10~150 DEG C and preferably in the range of 0~80 DEG C.

The reaction time can change according to the raw material, reagent or reaction temperature, but generally in the range of 30 minutes to 30 hours and preferably in the range of 1 to 10 hour.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example by suitably neutralizing the reactant mixture, if there is, filter out insoluble matter, evaporation of solvent, water is added into the reactant mixture, is subsequently added hydrophobic solvent (such as benzene, ether, ethyl acetate), to extract the compound, organic layer is washed with water, and is dried with anhydrous magnesium sulfate and solvent is evaporated off, and isolates the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

In step A5, the amino protecting group is removed, the compound (I) is made.

The removing of amino protecting group can change according to the type of the protection group, can be carried out with known method in common Synthetic Organic Chemistry as described below.

When the amino protecting group is C₁-C₆Alkanoyl group (preferably formoxyl or acetyl group)；C₆-C₁₀Arylcarbonyl group (preferably benzoyl)；Can be by halogen or three C₁-C₄The C of aIkylsilyl groups substitution₁-C₄Alkoxycarbonyl group (preferably methoxycarbonyl group, carbethoxyl group, tertbutyloxycarbonyl, 2- trimethyl silyls carbethoxyl group, the bromo- tertbutyloxycarbonyls of 2- or the bromo- tertbutyloxycarbonyl of 2,2- bis-)；The C that can be replaced by methoxyl group or nitro₂-C₅Chain ene keto carbonyl group (optimal ethylene oxygen carbonyl) or the C that can be replaced by methoxyl group or nitro₇-C₁₅During any one group in arylalkyloxycarbonyl group (preferably benzyloxycarbonyl group, (1- phenyl) benzyloxycarbonyl group, 9- anthryls methoxycarbonyl group, p- methbxybenzyl-oxycarbonyl or p- nitrobenzyloxycarbonyl), it can be removed by with acid treatment in atent solvent or aqueous solvent.At this point it is possible to which the form of salt obtains the purpose product.

Acid used can be such as any one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid and preferred hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid acid.

Solvent for use does not have specific restriction, as long as they disturbing reaction and can not dissolve a certain amount of raw material, they can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Or ester such as methyl acetate or ethyl acetate；Alcohol such as methanol, ethanol, propyl alcohol, isopropanol or butanol；Acid amides such as formamide, dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide；Sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone；Aliphatic acid such as formic acid or acetic acid；Or the aqueous mixture of water or above-mentioned solvent, preferably halogenated hydrocarbons, ether, alcohol, aliphatic acid；The aqueous mixture of water or above-mentioned solvent, and more preferably halogenated hydrocarbons (particularly dichloromethane), ether (particularly tetrahydrofuran Huo dioxanes), aliphatic acid (particularly acetic acid), the aqueous mixture of water or above-mentioned solvent.

The reaction temperature can change according to the raw material, solvent or acid used, but generally in the range of -10~150 DEG C and preferably in the range of 0~60 DEG C.

The reaction time can change according to the raw material, solvent or acid used, but generally in the range of 5 minutes to 20 hours and preferably in the range of 10 minutes to 5 hours.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.The purpose product being for example settled out by filtering in the reactant mixture, or by suitably neutralizing the reactant mixture, evaporation of solvent, water is added into the reactant mixture, hydrophobic solvent (such as benzene, ether, ethyl acetate) is subsequently added, to extract the compound, organic layer is washed with water, dried with anhydrous magnesium sulfate and solvent is evaporated off, isolate the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

When the amino protecting group is alkanoyl, aryl carbonyl, alkoxy carbonyl group, chain ene keto carbonyl, aryl dicarbapentaborane, aralkyl or arylalkyloxycarbonyl group, it can be removed by with alkali process in atent solvent or aqueous solvent.

Alkali used can be such as alkali carbonate such as sodium carbonate, potassium carbonate or lithium carbonate；Alkali metal hydrogencarbonate such as sodium acid carbonate, saleratus or lithium bicarbonate；Alkali metal hydride such as lithium hydride, sodium hydride or hydrofining；Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide；Alkali metal alkane alkoxide such as sodium methoxide, caustic alcohol, potassium tert-butoxide or lithium methoxide；Alkali metal mercaptide such as sodium methyl mercaptide or ethyl mercaptan sodium, more preferably alkali carbonate (particularly sodium carbonate or potassium carbonate), alkali metal hydroxide (particularly sodium hydroxide or potassium hydroxide), alkali metal alkane alkoxide (particularly sodium methoxide, caustic alcohol or potassium tert-butoxide) or organic amine (particularly hydrazine or methylamine).

Solvent for use does not have specific restriction, as long as they disturbing reaction and can not dissolve a certain amount of raw material, they can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Alcohol such as methanol, ethanol, propyl alcohol, isopropanol or butanol；Acid amides such as dimethyl acetamide or hexamethyl phosphoramide；Sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone；Or the aqueous mixture of above-mentioned solvent, it is preferred that halogenated hydrocarbons, ether, the aqueous mixture of alcohol or above-mentioned solvent, and the more preferably aqueous mixture of ether (particularly tetrahydrofuran Huo dioxanes), alcohol (particularly methanol or ethanol) or above-mentioned solvent.

The reaction temperature can change according to the raw material, solvent or alkali used, but generally in the range of -10~150 DEG C and preferably in the range of 0~50 DEG C.

The reaction time can change according to the raw material, solvent or alkali used, but generally in the range of 30 minutes to 20 hours and preferably in the range of 1 to 5 hour.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.The product being for example settled out by being filtered in reactant mixture, or pass through evaporation of solvent, adding water makes water layer in alkalescence to filter out the product of precipitation, or add hydrophobic solvent (such as benzene, ether, ethyl acetate), to extract the compound, organic layer containing purpose product is washed with water, and is dried with anhydrous magnesium sulfate and solvent is evaporated off, and obtains the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

When the amino protecting group is tert-butoxycarbonyl group, it can also be removed by with silyl compound or lewis acid processing in atent solvent.

Silyl compound used can be such as trimethylsilyl chloride, trimethylsilyl iodide or trimethylsilyl triflate, and lewis acid used can be aluminium chloride.

Solvent for use does not have specific restriction, as long as they disturbing reaction and can not dissolve a certain amount of raw material, they can be such as halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride；Ether such as ether, tetrahydrofuran Huo dioxanes；Or nitrile such as acetonitrile, preferably halogenated hydrocarbons (particularly dichloromethane or chloroform) or nitrile (particularly acetonitrile).

The reaction temperature can change according to the raw material, reagent or solvent, but generally in the range of -20~100 DEG C and preferably in the range of 0~50 DEG C.

The reaction time can change according to the raw material, reagent, solvent or the reaction temperature, but generally in the range of 10 minutes to 10 hours and preferably in the range of 30 minutes to 3 hours.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example pass through evaporation of solvent, water is added into reactant mixture to be made water layer in alkalescence and filters out the product of precipitation, or add hydrophobic solvent (such as benzene, ether, ethyl acetate), to extract the compound, organic layer containing purpose product is washed with water, dried with anhydrous magnesium sulfate and solvent is evaporated off, isolate the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

In the case where the amino protecting group is allyloxycarbonyl, it can include the removing of the conditions such as solvent, reaction temperature and time with the similar reaction condition of aromatic alkyl group is removed through palladium and triphenylphosphine or nickel carbonyl catalytic hydrogenation.

It is aralkyl or C in the amino protecting group₇-C₁₁In the case of arylalkyloxycarbonyl group, it can be by being handled in atent solvent and (preferably carrying out catalytic hydrogenation in the presence of a catalyst) or easily removed with oxidant with reducing agent.

Solvent used is not particularly limited in reaction in the catalytic hydrogenation to remove the protection group, as long as they do not participate in reaction and can be such as aliphatic hydrocarbon such as hexanes or hexamethylene；Aromatic hydrocarbon such as toluene, benzene or dimethylbenzene；Ether such as ether, tetrahydrofuran Huo dioxanes；Ester such as ethyl acetate or propyl acetate；Alcohol such as methanol, ethanol or isopropanol；Aliphatic acid such as formic acid and acetic acid；Or the aqueous mixture of these organic solvents.Preferred fat hydrocarbon, aromatic hydrocarbon, ether, ester, alcohol, the aqueous mixture of aliphatic acid or these solvents, and the more preferably aqueous mixture of alcohol (particularly methanol or ethanol), aliphatic acid (particularly formic acid or acetic acid) or these solvents.

Used catalyst does not have specific restriction, as long as it is usually used in catalytic hydrogenation and can be such as palladium-carbon, Raney nickel, rhodium-aluminum oxide or palladium-barium sulfate.It is preferred that palladium-carbon or Raney nickel.

The pressure of the hydrogen does not have a specific restriction, but generally in 1~10 barometric pressure range and preferably 1 atmospheric pressure.

The reaction temperature can change according to the raw material, solvent or catalyst used, but generally in the range of 0~100 DEG C and preferably in the range of 10~50 DEG C.

The reaction time can change according to the raw material, solvent, catalyst used or the reaction temperature, but generally in the range of 15 minutes to 10 hours and preferably in the range of 30 minutes to 3 hours.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example by filtering out evaporation of solvent after catalyst, add water, make water layer in alkalescence and filter out the product of precipitation, or by adding hydrophobic solvent (such as benzene, ether, ethyl acetate), to extract the compound, organic layer containing the purpose product is washed with water, and is dried with anhydrous magnesium sulfate and solvent is evaporated off, and isolates the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

Solvent used does not have specific restriction in the oxidation reaction of the removing protection group, as long as they do not participate in reaction and can be such as ketone such as acetone；Halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride；Nitrile such as acetonitrile；Ether such as ether, tetrahydrofuran Huo dioxanes；Acid amides such as dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide；Sulfoxide such as dimethyl sulfoxide；Or the aqueous mixture of these organic solvents.It is preferred that any one of ketone, halogenated hydrocarbon, nitrile, ethers, amide-type, aqueous mixture of sulfoxide type or these solvents, and the more preferably aqueous mixture of ketone (particularly acetone), halogenated hydrocarbon (particularly dichloromethane), nitrile (particularly acetonitrile), amide-type (particularly hexamethyl phosphoramide), sulfoxide type (particularly dimethyl sulfoxide) or these solvents.

Oxidant used can be such as potassium peroxydisulfate, sodium peroxydisulfate, ammonium ceric nitrate (CAN) or 2, chloro- 5, the 6- dicyano p-benzoquinones (DDQ) of 3- bis-, and preferably ammonium ceric nitrate (CAN) or 2, chloro- 5, the 6- dicyano p-benzoquinones (DDQ) of 3- bis-.

The reaction temperature can change according to the raw material, solvent or oxidant used, but generally in the range of 0~150 DEG C and preferably in the range of 10~50 DEG C.

The reaction time can change according to the compound, solvent or oxidant used, but generally in the range of 15 minutes to 24 hours and preferably in the range of 30 minutes to 5 hours.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example by filtering out evaporation of solvent after oxidant, adding water makes water layer in alkalescence and filters out the product of precipitation, or by adding hydrophobic solvent (such as benzene, ether, ethyl acetate), to extract the compound, organic layer containing the purpose product is washed with water, dried with anhydrous magnesium sulfate and solvent is evaporated off, isolate the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

Method B is the wherein X in method A in midbody compound (XVIII) for the synthetic method of the compound (XVIIIa) of oxygen.

In step B1, the compound (XVIIIa) is prepared by the way that the compound of the compound (XV) and formula (XVIIa) is carried out into reaction.

When y is the hydroxyl group, the reaction is according to Bull.Chem.Soc.Jap., 40, the reactions of Mitsunobu described in 2380 (1967) are carried out, i.e. in the presence of phosphine-compound and azo-compound, in atent solvent, the compound (XV) is subjected to dehydrogenative condensation with corresponding compound (XVIIa).

Solvent for use does not have specific restriction, as long as they disturbing reaction and can not dissolve a certain amount of raw material, they can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether.Preferred fat hydrocarbon, aromatic hydrocarbon or ether, and more preferably ether (particularly ether or tetrahydrofuran).

Phosphine-compound used can be such as three C₁-C₆Alkylphosphines such as trimethyl-phosphine, triethyl phosphine, tripropyl phosphine, tributylphosphine, three amyl group phosphines or three hexyl phosphines；Three C₆-C₁₀Aryl phosphine such as triphenylphosphine, three indenyl phosphines or three naphthyl phosphines；Or with C₁-C₄Three C of alkyl substituent₆-C₁₀Aryl phosphine such as tolyl diphenylphosphine, trimethylphenyl phosphine, three base phosphines, three fourth Phenylphosphines or three -6- ethyl -2- naphthyl phosphines.It is preferred that three C₁-C₆Alkylphosphines (particularly trimethyl-phosphine, triethyl phosphine, tripropyl phosphine or tributylphosphine) or three C₆-C₁₀Aryl phosphine (particularly triphenylphosphine, three indenyl phosphines or three naphthyl phosphines), and more preferably three C₆-C₁₀Aryl phosphine (particularly triphenylphosphine).

Azo-compound used can be such as C of azoformic acid two₁-C₄Arrcostab such as azo acid dimethyl ester, diethyl azodiformate, azoformic acid dipropyl or azoformic acid dibutyl ester and preferably azo acid dimethyl ester or diethyl azodiformate.

The reaction temperature can change according to the raw material or reagent, but generally in the range of -10~100 DEG C and preferably in the range of 0~50 DEG C.

The reaction time can change according to the raw material, reagent or reaction temperature, but generally in the range of 15 minutes to 48 hours and preferably in the range of 30 minutes to 24 hours.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example by filtering out insoluble matter that may be present and evaporation of solvent, or by adding water into residue after removal of the solvent, add hydrophobic solvent (such as benzene, ether, ethyl acetate), to extract the compound, it is washed with water, dried with anhydrous magnesium sulfate and solvent is evaporated off, obtain the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

When Y is leaving group, by the presence of a base, in atent solvent, compound (XV) and corresponding compound (XVIIa) is subjected to reaction and prepare the compound (XVIIIa).

Solvent for use does not have specific restriction, as long as it does not disturb described react simultaneously can dissolve a certain amount of raw material.They can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Acid amides such as formamide, dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide；Or sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone.Preferred amide or sulfoxide, and more preferably acid amides (particularly dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide).

Alkali used can be such as alkali carbonate such as sodium carbonate, potassium carbonate or lithium carbonate；Alkali metal hydrogencarbonate such as sodium acid carbonate, saleratus or lithium bicarbonate；Alkali metal hydride such as lithium hydride, sodium hydride or hydrofining；Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide；Alkali metal alkane alkoxide such as sodium methoxide, caustic alcohol, potassium tert-butoxide or lithium methoxide；Alkali metal mercaptide such as sodium methyl mercaptide or ethyl mercaptan sodium；Organic amine such as triethylamine, tri-butylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4- (N, N- dimethylamino) pyridine, DMA, N, N- diethylanilines, 1,5- diazabicyclos [4,3,0] nonyl- 5- alkene, 1,4- diazabicyclos [2,2,2] octane (DABCO) or 1,8- diazabicyclo [5,4,0] 11-7- alkene (DBU)；Lithium alkylide such as lithium methide, ethyl-lithium or butyl lithium；Alkyl lithamide such as lithium diisopropylamide or lithium dicyclohexylamide.Preferred alkali metal carbonate, alkali metal hydride or alkali metal hydroxide, and more preferably alkali metal hydride (particularly sodium hydride).

The reaction time can change according to the raw material, reagent or reaction temperature, but generally in the range of 30 minutes to 20 hours and preferably in the range of 1 to 5 hour.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example suitably neutralize the reactant mixture, if there is, filter out insoluble matter, evaporation of solvent, water is added into the residue, hydrophobic solvent (such as benzene, ether, ethyl acetate) is added to extract the compound, the organic layer containing the purpose compound is washed with water, dried with anhydrous magnesium sulfate and solvent is evaporated off, isolate the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

Method C is the method for another synthesis compound (XV), and compound (XV) is the intermediate in method A or the raw material in method B.

In step C1, by by the compound of formula (XIX) and diazonium C₁-C₄Alkane reaction prepares formula (XX) compound.

Diazonium C₁-C₄Alkane can be any one of diazomethane, aziethane, diazonium propane or diazonium butane and preferred diazomethane.

Solvent for use does not have specific restriction, as long as it does not disturb described react simultaneously can dissolve a certain amount of raw material.They can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Ester such as methyl acetate or ethyl acetate；Or the mixture of above-mentioned solvent.It is preferred that halogenated hydrocarbons, ether, the mixture of ester or above-mentioned solvent, and the more preferably mixture of ether (particularly ether), ester (particularly ethyl acetate) or above-mentioned solvent.

The reaction temperature can change according to the raw material and reagent, but generally in the range of -10~100 DEG C and preferably in the range of 10~50 DEG C.

The reaction time can change according to the raw material, reagent or reaction temperature, but generally in the range of 10 minutes to 10 hours and preferably in the range of 15 minutes to 3 hours.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.The purpose compound is for example isolated by evaporation of solvent.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

In step C2, by the presence of a base, in atent solvent, the compound (XX) and azanol reaction are prepared to formula (XXI) compound.

The solvent and alkali are as described in step A1.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example pass through evaporation of solvent, water is added into residue to be made water layer in acidity and filters the product of precipitation, or by adding water into the reactant mixture, make water layer in acidity, hydrophobic solvent (such as benzene, ether, ethyl acetate) is added, to extract the purpose compound, the organic layer of extraction is washed with water, dried with anhydrous magnesium sulfate and solvent is evaporated off, isolate the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

In step C3, the compound (XV) is prepared by the way that the compound (XXI) and alkali are reacted in atent solvent.

Solvent for use does not have specific restriction, as long as it does not disturb described react simultaneously can dissolve a certain amount of raw material.They can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Or ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Acid amides such as formamide, dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide；Sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone；Or water.Preferred amide, sulfoxide or water, and more preferably water.

Alkali used can be such as alkali carbonate such as sodium carbonate, potassium carbonate or lithium carbonate；Alkali metal hydrogencarbonate such as sodium acid carbonate, saleratus or lithium bicarbonate；Alkali metal hydride such as lithium hydride, sodium hydride or hydrofining；Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide；Organic amine such as triethylamine, tri-butylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4- (N, N- dimethylamino) pyridine, DMA, N, N- diethylanilines, 1,5- diazabicyclos [4,3,0] nonyl- 5- alkene, 1,4- diazabicyclos [2,2,2] octane (DABCO) or 1,8- diazabicyclo [5,4,0] 11-7- alkene (DBU)；Lithium alkylide such as lithium methide, ethyl-lithium or butyl lithium；Or alkyl lithamide such as lithium diisopropylamide or lithium dicyclohexylamide.Preferred alkali metal carbonate, alkali metal hydrogencarbonate or alkali metal hydroxide, and more preferably alkali metal hydroxide (particularly sodium hydroxide or potassium hydroxide).

The reaction temperature can change according to the raw material and reagent, but generally in the range of 0~150 DEG C and preferably in the range of 10~100 DEG C.

The reaction time can change according to the raw material, reagent or reaction temperature, but generally in the range of 10 minutes to 10 hours and preferably in the range of 15 minutes to 5 hours.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example by making the product or make the reactant mixture in acidity that the reactant mixture is in acid and filtering is settled out, hydrophobic solvent (such as benzene, ether, ethyl acetate) is added to extract the compound, organic layer containing the purpose compound is washed with water, dried with anhydrous magnesium sulfate and solvent is evaporated off, isolate the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

Method D is that the substituent on the ring A of midbody compound (XVIII) in wherein method A contains R¹ _aThe compound (XXIII) synthetic method.

In step D1, by the presence of a base, in atent solvent, by the compound (XXII) and halo C₁-C₆Alkane, carbon dioxide, carbon disulfide, two C₁-C₆Alkyl disulfide, the C of carbonic acid two₁-C₆Arrcostab, S- (trifluoromethyl) dibenzothiophenes father-in-law fluoroform sulphonate or S- (trifluoromethyl) -3,7- dinitro dibenzothiophenes father-in-law fluoroform sulphonates (preferably halo C₁-C₆Alkane or carbon dioxide) reaction prepare the compound (XXIII).

Halo C₁-C₆Alkane can be such as chloromethanes, bromomethane, iodomethane, chloroethanes, iodoethane, N-Propyl Bromide, iodobutane, iodopentane or iodohexane.It is preferred that bromomethane or iodomethane, and more preferably iodomethane.

Two C₁-C₆Alkyl disulfide can be such as dimethyl disulphide, diethyl disulfide, dipropyl disulfide compound, dibutyl disulphide, diamyl disulfide compound or dihexyl disulphide, and preferably dimethyl disulphide or diethyl disulfide.

The C of carbonic acid two₁-C₆Arrcostab can be such as dimethyl carbonate, diethyl carbonate, dipropyl carbonate, dimethyl isopropyl ester, dibutyl carbonate, carbonic acid di-sec-butyl ester, dimethyl dicarbonate butyl ester, diamyl carbonate or carbonic acid dihexyl, and preferably dimethyl carbonate or diethyl carbonate.

Solvent for use does not have specific restriction, as long as it does not disturb described react simultaneously can dissolve a certain amount of raw material.They can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Diamines such as N, N, N ', N '-tetra-methylenedimine；Acid amides such as formamide, dimethylformamide, dimethyl acetamide, hexamethyl phosphoramide or hexamethyl phosphoramide；Or sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone.It is preferred that ether, acid amides or sulfoxide, and more preferably ether (particularly tetrahydrofuran).

Alkali used can be such as alkali metal hydride such as lithium hydride, sodium hydride or hydrofining；Lithium alkylide such as lithium methide, ethyl-lithium, butyl lithium or s-butyl lithium；Or alkyl lithamide such as lithium diisopropylamide, lithium dicyclohexylamide, two (trimethyl silyl) lithamides, two (trimethyl silyl) ammonification potassium or two (trimethyl silyl) sodium amides.It is preferred that lithium alkylide (particularly butyl lithium) or alkyl lithamide (particularly lithium diisopropylamide).

The reaction temperature can change according to the raw material and reagent, but generally in the range of -100~30 DEG C and preferably in the range of -70~0 DEG C.

The reaction time can change according to the raw material, reagent or reaction temperature, but generally in the range of 5 minutes to 10 hours and preferably in the range of 10 minutes to 5 hours.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example pass through evaporation of solvent, or pass through evaporation of solvent, water is added into the residue, hydrophobic solvent (such as benzene, ether, ethyl acetate) is added to extract the compound, the organic layer of extraction is washed with water, dried with anhydrous magnesium sulfate and solvent is evaporated off, isolate the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

When the purpose compound described in this step is used for next step, then isolated or purified need not be carried out after the completion of the reaction.

Method E is the compound (XXVII) that the substituent on the ring A of midbody compound (XVIII) in wherein method A contains carbamoyl and the compound (synthetic method of (XXVIII) for being used as raw material in method F.

In step E1, by the presence of a base, in atent solvent, the compound (XXIV) and the reaction of formula (XXV) compound are prepared into the compound (XXVI).When X is sulphur atom in compound (XXVI), it is the starting compound (XXVIII) in method F.

Solvent for use does not have specific restriction, as long as it does not disturb described react simultaneously can dissolve a certain amount of raw material.They can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Diamines such as N, N, N ', N '-tetra-methylenedimine；Acid amides such as formamide, dimethylformamide, dimethyl acetamide, hexamethyl phosphoramide or hexamethyl phosphoramide；Or sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone.Preferred amide or sulfoxide, and more preferably acid amides (particularly dimethylformamide).

Alkali used can be such as alkali carbonate such as sodium carbonate, potassium carbonate or lithium carbonate；Alkali metal hydrogencarbonate such as sodium acid carbonate, saleratus or lithium bicarbonate；Alkali metal hydride such as lithium hydride, sodium hydride or hydrofining；Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide；Organic amine such as triethylamine, tri-butylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4- (N, N- dimethylamino) pyridine, DMA, N, N- diethylanilines, 1,5- diazabicyclos [4,3,0] nonyl- 5- alkene, 1,4- diazabicyclos [2,2,2] octane (DABCO) or 1,8- diazabicyclo [5,4,0] 11-7- alkene (DBU)；Lithium alkylide such as lithium methide, ethyl-lithium or butyl lithium；Or alkyl lithamide such as lithium diisopropylamide or lithium dicyclohexylamide.Preferred alkali metal carbonate, alkali metal hydrogencarbonate or alkali metal hydroxide, and more preferably alkali carbonate (particularly sodium carbonate, potassium carbonate or lithium carbonate).

The reaction time can change according to the raw material, reagent or reaction temperature, but generally in the range of 30 minutes to 30 hours and preferably in the range of 1 to 20 hour.

In step E2, by the way that in atent solvent, prepared by the compound (XXVI) and the reaction of ammonia or concentrated ammonia solution into the compound (XXVIII).When X is sulphur atom in compound (XXVII), then the substituent on the ring A in the compound (XVIII) contains carbamoyl group.

Solvent for use does not have specific restriction, as long as it does not disturb described react simultaneously can dissolve a certain amount of raw material.They can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Or ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Alcohol such as methanol, ethanol, propyl alcohol, isopropanol, butanol or isobutanol；Diamines such as N, N, N ', N '-tetra-methylenedimine；Acid amides such as formamide, dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide；Or sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone.It is preferred that ether or alcohol, and more preferably alcohol (particularly methanol or ethanol).

The reaction time can change according to the raw material, reagent or reaction temperature, but generally in the range of 1 to 30 hour and preferably in the range of 3 to 20 hours.

In step E3, also it can prepare the compound (XXVII) by the compound (XXIV) and ammonia are condensed in atent solvent and can be carried out under the conditions of the conventional peptide symthesis method such as azide method, active ester method, mixed anhydride method or condensation method (preferably mixed anhydride method).

In above-mentioned azide method, at a temperature of -10~100 DEG C (preferably 0~50 DEG C), in atent solvent (such as acid amides such as formamide, dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide, it is preferred that dimethylformamide) in, handle the compound (XXIV) with hydrazine.By being reacted with nitrite (ester), then with ammonia treatment, synthesized amino acid hydrazines is transformed into azide.

Nitrite (ester) compound used can be such as alkali metal nitrites salts such as natrium nitrosum or alkyl nitrite such as isoamyl nitrite.

The reaction is preferably carried out in atent solvent, and the atent solvent can be acid amides such as formamide, dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide；Sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone；Or pyrrolidones such as 1-METHYLPYRROLIDONE, preferred amide (particularly dimethylformamide).

In addition, the 2nd step (forming the reaction of azide and the reaction with ammonia) in the method can be carried out by one kettle way.

The reaction temperature can change according to the raw material or reagent, but it is typically to be carried out in the range of -70~50 DEG C (preferably -50~0 DEG C) to form the reaction of azide, and with the reaction of ammonia is carried out in the range of -70~50 DEG C (preferably -10~10 DEG C).

The reaction time can change according to the raw material, reagent or reaction time, but it is typically to be carried out in the range of 5 minutes to 3 hours (preferably 10 minutes to 1 hour) to form the reaction of azide, and is the progress more than 5 hours and preferably in the range of 10 hours to 5 days with the reaction of ammonia.

The active ester method is by compound (XXIV) and being completed in atent solvent with described in ester formation agent treatment in atent solvent with the active ester synthesized by ammonia treatment.

Solvent used does not have specific restriction in two-step reaction, as long as it does not disturb described react simultaneously can dissolve a certain amount of raw material.They can be such as halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Acid amides such as formamide, dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide；Or nitrile such as acetonitrile.It is preferred that ether (special tetrahydrofuran) or acid amides (particularly dimethylformamide).

Active ester formation reagent used can be such as N- hydroxy compounds such as n-hydroxysuccinimide, I-hydroxybenzotriazole or N- hydroxyl -5- ENBs -2,3- dicarboximides (dicarboximide) or disulphide such as pyridyl disulfide.The active esterifying reaction is preferably carried out in the presence of condensing agent such as dicyclohexyl carbodiimide, carbonyl dimidazoles or triphenylphosphine.

The reaction temperature can change according to the raw material or reagent, but the active esterifying reaction is typically to be carried out in the range of -70~150 DEG C (preferably -10~100 DEG C), and with the reaction of ammonia is carried out in the range of -20~100 DEG C (preferably 0~50 DEG C).

The reaction time can change according to the raw material, reagent or reaction time, but the two-step reaction is typically to be carried out in the range of 30 minutes to 80 hours (preferably 1 to 48 hour).

The mixed anhydride method is by the presence of a base, handling the compound (XXIV) with mixed acid anhydride in atent solvent and being completed in atent solvent with the mixed acid anhydride produced by ammonia treatment.

Synthesize solvent for use in the reaction of mixed acid anhydride and do not have specific restriction, as long as it does not disturb described react simultaneously can dissolve a certain amount of raw material.They can be such as halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Or acid amides such as formamide, dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide, and preferably ether (particularly tetrahydrofuran).

The mixed acid anhydride formation reagent can be such as C₁-C₄- halogenated alkyl carbonic ester such as ethyl chloride carbonic ester or isobutyl chloride carbonic ester；C₁-C₅Alkane carboxylic acid halides such as pivalyl chloride；Or C₁-C₄Alkyl cyano group phosphate or C₆-C₁₄Arylamino group phosphate such as diethyl cyano group phosphate or diphenyl cyano group phosphate.It is preferred that C₁-C₄Halogenated alkyl carbonic ester (particularly isobutyl chloride carbonic ester).

Alkali used can be such as alkali carbonate such as sodium carbonate, potassium carbonate or lithium carbonate；Or organic amine such as triethylamine, tri-butylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4- (N, N- dimethylamino) pyridine, DMA, N, N- diethylanilines, 1,5- diazabicyclos [4,3,0] nonyl- 5- alkene, 1,4- diazabicyclos [2,2,2] octane (DABCO) or 1,8- diazabicyclos [5,4,0] 11-7- alkene (DBU), and preferably organic amine (particularly triethylamine).

The reaction temperature for preparing mixed anhydride reaction can change according to the raw material or reagent, but generally in the range of -50~100 DEG C (preferably -10~50 DEG C).

The reaction time for preparing mixed anhydride reaction can change according to the raw material, reagent or reaction temperature, but generally in the range of 5 minutes to 20 hours (preferably 10 minutes to 10 hours).

Mixed acid anhydride solvent used in being reacted with ammonia does not have specific restriction, as long as it does not disturb described react simultaneously can dissolve a certain amount of raw material.They can be such as ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Or acid amides such as formamide, dimethylformamide, dimethyl acetamide or hexamethyl phosphoramide, and preferably ether (particularly tetrahydrofuran).

The reaction temperature that the mixed acid anhydride reacts with ammonia can change according to the raw material or reagent, but generally in the range of -30~100 DEG C (preferably 0~80 DEG C).

The reaction time that the mixed acid anhydride reacts with ammonia can change according to the raw material, reagent or reaction time, but generally in the range of 5 minutes to 24 hours (preferably 10 minutes to 5 hours).

The condensation reaction is by the presence of condensing agent, in atent solvent, and the compound (XXIV) is directly handled with ammonia to complete.

Condensing agent used can be such as dicyclohexyl carbodiimide, carbonyl dimidazoles or 1- methyl -2- chloropyridines father-in-law iodide-triethylamine, and preferably dicyclohexyl carbodiimide.

This reaction can be carried out under the similar reaction condition of above-mentioned synthesizing activity ester.

Method F is the method for the compound (XXIX) for containing the trifluoromethyl group as substituent on another synthesis wherein in method a midbody compound (XVIII) ring A.

In step F1, according to Chemistry Letters, 827 (1992) methods describeds, by atent solvent by the compound (XXVIII) and trifluoro dihydro tetrabutylammonium (TBA⁺H₂F₃ ^-) and DBDMH (DBH) the reaction synthesis compound (XXIX).

Solvent for use does not have specific restriction, as long as it does not disturb described react simultaneously can dissolve a certain amount of raw material.They can be such as halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Or ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether, and preferably halogenated hydrocarbons (particularly dichloromethane).

The reaction temperature can change according to the raw material or reagent, but generally in the range of -30~100 DEG C and preferably in the range of 0~50 DEG C.

The reaction time can change according to the raw material, reagent or reaction temperature, but generally in the range of 10 minutes to 5 hours and preferably in the range of 30 minutes to 3 hours.

After the completion of reaction, the purpose compound of this step is isolated in the reactant mixture according to a conventional method.For example pass through evaporation of solvent, water is added into the reactant mixture, hydrophobic solvent (such as benzene, ether, ethyl acetate) is added to extract the compound, extract is washed with water, dried with anhydrous magnesium sulfate and solvent is evaporated off, isolate the purpose compound.If desired, gained purpose compound can be purified through recrystallization, reprecipitation or chromatography.

Method G is the method for the compound (XXXI) for containing the cyano group as substituent on another synthesis wherein in method a midbody compound (XVIII) ring A.

In step G1, by the way that prepared by the compound (XXX) and dehydrating agent reaction into the compound (XXXI) in atent solvent.

Solvent for use does not have specific restriction, as long as it does not disturb described react simultaneously can dissolve a certain amount of raw material.They can be such as aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether；Aromatic hydrocarbon such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, chlorobenzene or dichlorobenzene；Ether such as ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes, dimethoxy-ethane or diethylene glycol dimethyl ether；Ester such as methyl acetate or ethyl acetate；Ketone such as acetone；Acid amides such as formamide, dimethylformamide, dimethyl acetamide, hexamethyl phosphoramide or hexamethylphosphorictriamide；Or sulfoxide such as dimethyl sulfoxide or tetramethylene sulfone.It is preferred that ether, acid amides or sulfoxide, and more preferably acid amides (particularly dimethylformamide).

Dehydrating agent used can be such as phosphoryl chloride phosphorus oxychloride, TFAA, mesyl chloride, paratoluensulfonyl chloride or phosphorus pentoxide, and preferably phosphoryl chloride phosphorus oxychloride.

The reaction temperature can change according to the raw material or reagent, but generally in the range of -30~100 DEG C and preferably in the range of -10~30 DEG C.

The reaction time can change according to the raw material, reagent or reaction temperature, but generally in the range of 5 minutes to 10 hours and preferably in the range of 10 minutes to 3 hours.

It is known compound as the compound (II) of MAOI; or by as described in step A4; the compound (XVI) and general formula compound are reacted; and; if desired; amino is removed as described in step 5 or the synthesis of alkylamino protection group is obtained

HX-(CH₂)_n-R⁴ _a

(XVIIb) wherein X is as described above, R⁴ _aExcept its amino and list C₁-C₄Alkylamino group is by remaining and R beyond protection² _aIt is identical,

In addition, the compound with oxygen atom can be by the way that as described in step B1, the compound (XVI) and general formula compound be reacted on X in the compound (II); and; if desired, removing amino or the synthesis of alkylamino protection group are obtained as described in step A5

Y-(CH₂)_n-R⁴ _a

(XVIIc) wherein R⁴ _aIt is as described above with Y.

Because isoxazole derivatives of the present invention (I) and (II) have significant Type B and A MAO-B Bs inhibitory action (inhibitory action to monoamine oxidase B is particularly significant), therefore it can be used as the therapeutic agent or prophylactic of Parkinson's, depression and alzheimer's disease (particularly Parkinson's), and with relatively low toxicity.

[optimum implementation of the present invention]

The present invention is described in further detail in the following example, preparation and test method part, but the present invention is not limited in these embodiments.

Chloro- 1,2- benzo isoxazole hydrochlorates (a) the 5- chloro-salicylic acid's ethyl esters of embodiment 13- (2- amino ethoxies) -5-

It is stirred at room temperature down, the concentrated sulfuric acid (40ml) is added into 5- chloro-salicylic acids (500g) ethanol (2L) suspension.After reactant mixture is flowed back 12 hours, remove solvent under reduced pressure and residue is dissolved in ethyl acetate.Organic layer is washed with 10%NaCl solution and 4% sodium bicarbonate solution, is then evaporated under reduced pressure, is dried with anhydrous magnesium sulfate.After filtering, solvent is removed under reduced pressure, obtain title compound described in pale yellowish oil (514g, 88%).

IR composes (KBr) ν_maxcm^-1：680,1475

H NMR spectroscopy (DMSO-d₆)δppm：1.42 (3H, t, J=7.3Hz),

4.43 (2H, q, J=7.3Hz), 6.93 (1H, d, J=7.3Hz), 7.35 (1H, dd, J=7.3Hz, J=2.5Hz),

7.82 (1H, d, J=2.5Hz), 11.80 (1H.s) (b) 5- chlorine water Yankee carboxylics oximes acid (salicylcarbohydroxamic acid)

Hydroxylamine hydrochloride (197g) is dissolved in water (400ml) and is cooled to 5 DEG C.Methanol (1.5L) solution of potassium hydroxide (545g) is added, under mutually synthermal stirring, methanol (400ml) solution of 5- chloro-salicylic acids ethyl ester (500g) is added dropwise.After stirring 30 minutes at a temperature of 5-10 DEG C, continue to stir 3 hours at room temperature.Remove solvent under reduced pressure and residue is dissolved in frozen water (6L).The pH of solution is adjusted to 2 with concentrated hydrochloric acid, through filtering the crystallization being settled out and being washed with water, title compound described in colorless crystals (438g, 93%) is obtained.

Fusing point：216-222℃

IR composes (KBr) ν_maxcm^-1：3127,1618,1577,1523,1492,1413；

H NMR spectroscopy (DMSO-d₆)δppm：6.96 (1H, d, J=7.3Hz),

7.43 (1H, dd, J=7.3Hz, J=2.5Hz), 9.31-9.52 (1H, brs), 10.88-11.03 (1H, brs),

11.66-11.87 (1H, brs) (c) 5- chloro-3-hydroxyl -1,2- benzoisoxazoles

Under 10-20 DEG C is stirred, thionyl chloride (100ml) is added dropwise to tetrahydrofuran (600ml) solution of 5- chlorine water Yankee carboxylics oxime sour (216g) is a variety of.After being stirred 2 hours at identical temperature, reactant mixture is evaporated under reduced pressure, residue is dissolved in dioxane (600ml) and is cooled to 0-5 DEG C.Triethylamine (383ml) is added into the reactant mixture and is stirred 1 hour at room temperature.Remove solvent under reduced pressure, frozen water (3L) is added into residue.The pH of mixture is adjusted to 2 with concentrated hydrochloric acid, the crystallization being settled out is filtered and is washed with water.Through being recrystallized in ethyl acetate, title compound described in colorless needle crystals shape (172g, 88%) is obtained.

Fusing point：219-222℃

IR composes (KBr) ν_maxcm^-1：3400-2000,1613,1560,1516；

H NMR spectroscopy (DMSO-d₆)δppm：7.43-7.72 (2H, m), 7.82 (1H, d, J=2.5Hz),

(10.78-11.02 1H, brs).(d) 2- (N- t-butoxycarbonyl aminos) ethanol

In under ice cooling and stirring, two dimethyl dicarbonate butyl esters (21.8g) are added into the tetrahydrofuran and water (1: 1,100ml) solution of 2- ethylaminoethanols (6.1g).By reactant mixture in being stirred at identical temperature 1 hour, then at room temperature, stir 5 hours.Ethyl acetate (200ml) is added into reactant mixture, is washed with water, organic layer is dried with anhydrous magnesium sulfate.After filtering, solvent is removed under reduced pressure, obtain title compound described in colorless oil (15.3g).

Rf：(hexamethylene: ethyl acetate=1: 1)：0.35；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 2.35-2.50 (1H, brs),

3.29 (2H, q, J=5.3Hz), 3.71 (2H, q, J=5.3Hz), 4.85-5.05 (1H, brs).(e) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1, the 2- benzoisoxazoles of -5-

In under ice cooling and stirring, diethyl azodiformate (0.57g) is added dropwise into triphenylphosphine (0.87g) tetrahydrofuran (10ml) solution.By reactant mixture in stirring 10 minutes at identical temperature, then 2- (N- t-butoxycarbonyl aminos) ethanol (0.48g) and 5- chloro-3-hydroxyls -1 are continuously added into reactant mixture, 2- benzoisoxazoles (0.51g), in stirring 10 minutes under ice cooling and are stirred 24 hours at room temperature.Remove solvent under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (4/1), through being recrystallized to give title compound described in colorless crystals (0.70g) in isopropanol.

Fusing point：106-107℃

IR composes (KBr) ν_maxcm^-1：3376,1706,1611,1541,1525；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.64 (2H, q, J=5.1Hz),

4.50 (2H, t, J=5.1Hz), 4.95 (1H, brs), 7.37 (1H, d, J=8.8Hz),

7 49 (1H, dd, J=8.8Hz, J=2.0Hz), 7.63 chloro- 1, the 2- benzo isoxazole hydrochlorates of (1H, d, J=2.0Hz) (f) 3- (2- amino ethoxies) -5-

4N- hydrochloric acid/dioxane solution of Isosorbide-5-Nitrae-(4.0ml) is added into 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles (0.50g) of -5- and is stirred 15 minutes at room temperature.Filter after the crystallization being settled out, washed with the dioxane of Isosorbide-5-Nitrae-, obtain title compound described in colorless crystals (0.38g).

Fusing point：217-221 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1612,1534,1519；

H NMR spectroscopy (DMSO-d₆)δppm：3.33 (2H, t, J=5.1Hz), 4.61 (2H, t, J=5.1Hz),

7.73 (2H, d, J=1.4Hz), 7.88 (1H, d, J=1.4Hz), 8.28 (3H, brs).

Embodiment 23- (2- amino ethoxies) -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1,2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, the title compound is made by 3- hydroxyls -1,2- benzoisoxazole and 2- (N- t-butoxycarbonyl aminos) ethanol, yield is 68%.

Fusing point：106-107℃

IR composes (KBr) ν_maxcm^-1：3326,1716,1707,1615,1536；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.51 (2H, t, J=5.1Hz), 4.90-5.05 (1H, brs), 7.26-7.66 (4H, m).(b) 3- (2- amino ethoxies) -1,2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3-, (title compound is made in 2- (N- t-butoxycarbonyl aminos) ethyoxyl -1,2- benzoisoxazole, and yield is 98%.

Fusing point：194-197 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1614,1541,1521；

H NMR spectroscopy (D₂O)δppm：3.60 (2H, t, J=5.1Hz), 4.94 (2H, t, J=5.1Hz),

7.41-7.80 (4H, m).

Embodiment 33- (3- amino propoxyl group) -1,2- benzo isoxazole hydrochlorates (a) 3- (N- t-butoxycarbonyl aminos) propyl alcohol

According to embodiment 1 (d) similar the method reaction and processing, the title compound (1.65g) is made by 3- aminopropanols (0.75g) and two dimethyl dicarbonate butyl esters (2.18).

Rf (hexamethylenes: ethyl acetate=1: 1)：0.35；

H NMR spectroscopy (CDCl₃)δppm：1.49 (9H, s), 1.70 (2H, q, J=5.9Hz),

2.85-2.95 (1H, brs), 3.33 (2H, q, J=5.9Hz), 3.70 (2H, q, J=5.9Hz),

4.65-4.90 (1H, brs) (b) 3- (3- (N- t-butoxycarbonyl aminos) propoxyl group) -1,2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, the title compound is made by 3- hydroxyls -1,2- benzoisoxazole and 3- (N- t-butoxycarbonyl aminos) propyl alcohol, yield is 75%.

Fusing point：59-60℃

IR composes (KBr) ν_maxcm^-1：3383,1690,1613,1539,1521；

H NMR spectroscopy (CDCl₃)δppm：1.44 (9H, s), 2.05-2.13 (2H, m),

3.36 (2H, q, J=6.3Hz), 4.52 (2H, t, J=5.9Hz), 4.70-4.85 (1H, brs),

7.25-7.65 (4H, m) (c) 3- (3- amino propoxyl group) -1,2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, the title compound is made by 3- (3- (N- t-butoxycarbonyl aminos) propoxyl group) -1,2- benzoisoxazoles, yield is 96%.

Fusing point：146-147 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1615,1541,1536；

H NMR spectroscopy (D₂O)δppm：2.29-2.36 (2H, m), 3.31 (2H, t, J=7.3Hz),

4.59 (2H, t, J=5.9Hz), 7.40-7.78 (4H, m).

Embodiment 43- (4- Aminobutoxies) -1,2- benzo isoxazole hydrochlorates (a) 4- (N- t-butoxycarbonyl aminos) butanol

According to embodiment 1 (d) similar the method reaction and processing, the title compound (1.80g) is made by 4- amino butanols (0.89g) and two dimethyl dicarbonate butyl esters (2.18).

Rf (hexamethylenes: ethyl acetate=1: 1)：0.35；

H NMR spectroscopy (CDCl₃)δppm：1.44 (9H, s), 1.55-1.65 (4H, m),

3.16 (2H, q, J=5.9Hz), 3.67 (2H, q, J=5.9Hz), 4.55-4.75 (1H, brs).(b) 3- (4- (N- t-butoxycarbonyl aminos) butoxy) -1,2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, the title compound is made by 3- hydroxyls -1,2- benzoisoxazole and 4- (N- t-butoxycarbonyl aminos) butanol, yield is 71%.

IR composes (KBr) ν_maxcm^-1：3321,1701,1615,1539,1509；

H NMR spectroscopy (CDCl₃)δppm：1.14 (9H, s), 1.62-1.74 (2H, m),

1.91-1.97 (2 H, m), 3.15-3.27 (2H, brs), 4.46 (2H, t, J=6.5Hz), 4.55-4.70 (1H, brs),

7.24-7.66 (4H, m) (c) 3- (4- Aminobutoxies) -1,2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, the title compound is made by 3- (4- (N- t-butoxycarbonyl aminos) butoxy) -1,2- benzoisoxazoles, yield is 97%.

Fusing point：138-139 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1613,1541；

H NMR spectroscopy (D₂O)δppm：1.88-1.97 (2H, m), 1.99-2.06 (2H, m),

3.14 (2H, t, J=7.6Hz), 4.50 (2H, t, J=6.1Hz), 7.39-7.78 (4H, m).

Fluoro- 1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 53- (2- amino ethoxies) -5- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) fluoro- 1,2- benzoisoxazoles of -5-

According to embodiment 1 (e) similar the method reaction and processing, the title compound is made by fluoro- 3- hydroxyls -1, the 2- benzoisoxazoles of 5- and 2- (N- t-butoxycarbonyl aminos) ethanol, yield is 60%

IR composes (KBr) ν_maxcm^-1：3338,1707,1623,1543,1534,1504；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.64 (2H, q, J=5.1Hz),

4.50 (2H, t, J=5.1Hz), 4.88-5.03 (1H, brs), 7.22-7.42 (3H, m).(b) fluoro- 1, the 2- benzo isoxazole hydrochlorates of 3- (2- amino ethoxies) -5-

According to embodiment 1 (f) similar the method reaction and processing, the title compound is made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) fluoro- 1,2- benzoisoxazoles of -5-, yield is 98%.

Fusing point：209-211 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1621,1606,1538,1505；

H NMR spectroscopy (D₂O)δppm：3.59 (2H, t, J=5.1Hz), 4.73 (2H, t, J=5.1Hz),

7.42-7.58 (3H, m).

Embodiment 63- (2- amino ethoxies) -5- methoxyl group -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- methoxyl group -1,2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, by 3- hydroxy-5-methyl Oxy-1s, the title compound is made in 2- benzoisoxazoles and 2- (N- t-butoxycarbonyl aminos) ethanol, and yield is 74%.

IR composes (KBr) ν_maxcm^-1：3255,1698,1615,1540,1508；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.65 (2H, q, J=5.1Hz), 3.86 (3H, s),

4.50 (2H, t, J=5.1Hz), 4.90-5.05 (1H, brs), 6.98 (1H, d, J=2.6Hz),

7.15 (1H, dd, J=9.2Hz, J=2.6Hz), 7.33 (1H, d, J=9.2Hz) (b) 3- (2- amino ethoxies) -5- methoxyl group -1,2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, the title compound is made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- methoxyl group -1,2- benzoisoxazoles, yield is 96%.

Fusing point：210-212 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1606,1538,1521,1505；

H NMR spectroscopy (D₂O)δppm：3.59 (2H, t, J=5.1Hz), 3.90 (3H, s),

4.71 (2H, t, J=5.1Hz), 7.22 (1H, d, J=2.6Hz), 7.32 (1H, dd, J=9.2Hz, J=2.6Hz),

7.48 (1H, d, J=9.2Hz)

Embodiment 73- (2- amino ethoxies) -5- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates (a) 5- cresotinic acid acetoacetic esters

According to embodiment 1 (a) similar the method reaction and processing, the title compound is made by 5- cresotinic acids, yield is 84%.(b) 5- methyl salicyls carboxylic oxime acid

According to embodiment 1 (b) similar the method reaction and processing, the title compound is made by 5- cresotinic acid acetoacetic esters, yield is 94%.

Fusing point：172-175 DEG C (decomposition)；

H NMR spectroscopy (DMSO-d₆)δppm：2.22 (3H, s), 6.78 (1H, d, J=8.6Hz),

7.17 (1H, d, J=8.6Hz), 7.50 (1H, s), 9.25 (1H, s), 11.33 (1H, s), 11.95 (1H, s).(c) 3- hydroxy-5-methyls base -1,2- benzoisoxazole

According to embodiment 1 (c) similar the method reaction and processing, the title compound is made by 5- methyl salicyl carboxylics oxime acid, yield is 94%.

Fusing point：95-97℃；

H NMR spectroscopy (CDCl₃)δppm：2.45 (3H, s), 7.13-7.43 (3H, m),

9.02-9.15 (1H, brs).(d) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- methyl isophthalic acids, 2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, the title compound is made by 3- hydroxy-5-methyl base -1,2- benzoisoxazoles and 2- (N- t-butoxycarbonyl aminos) ethanol, yield is 69%.

IR composes (KBr) ν_maxcm^-1：3367,1717,1614,1538-1522；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.45 (3H, s), 3.64 (2H, q, J=5.1Hz),

4.50 (2H, t, J=5.1Hz), 4.90-5.05 (1H, brs), 7.31-7.52 (3H, m) (e) 3- (2- amino ethoxies) -5- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- methyl isophthalic acids, the title compound is made in 2- benzoisoxazoles, and yield is 97%.

Fusing point：218-220 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1625,1612,1536,1502；

H NMR spectroscopy (DMSO-d₆)δppm：2.43 (3H, s), 3.26-3.41 (3H, m),

4.60 (2H, t, J=5.1Hz), 7.48-7.55 (3H, m), 8.32 (3H, brs)

Embodiment 83- (2- amino ethoxies) -5- nitro -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- nitro -1,2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction (being further continued for reaction 3 hours) and processing, by 3- hydroxyl -5- nitros -1, the title compound is made in 2- benzoisoxazoles and 2- (N- t-butoxycarbonyl aminos) ethanol, and yield is 74%.

Fusing point：136-137℃；

IR composes (KBr) ν_maxcm^-1：3346,1688,1624,1555,1531；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.67 (2H, q, J=5.1Hz),

4.55 (2H, t, J=5.1Hz), 4.87-5.05 (1H, brs), 7.56 (1H, d, J=9.2Hz),

8.46 (1H, dd, J=9.2Hz, J=2.2Hz), 8.62 (1H, d, J=2.2Hz) (b) 3- (2- amino ethoxies) -5- nitro -1,2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, the title compound is made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- nitro -1,2- benzoisoxazoles, yield is 99%.

Fusing point：228-231 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1620,1543,1519；

H NMR spectroscopy (DMSO-d₆)δppm：3.36 (2H, t, J=5.1Hz), 4.66 (2H, t, J=5.1Hz),

7.93 (2H, d, J=9.2Hz), 8.34 (3H, brs), 8.54 (1H, dd, J=9.2Hz, J=2.2Hz),

8.74 (1H, d, J=2.2Hz)

Chloro- 1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 93- (2- amino ethoxies) -7- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -7-

According to embodiment 1 (e) similar the method reaction and processing, the title compound is made by chloro- 1, the 2- benzoisoxazoles of 3- hydroxyls -7- and 2- (N- t-butoxycarbonyl aminos) ethanol, yield is 62%.

Fusing point：64-65℃；

IR composes (KBr) ν_maxcm^-1：3355,1714,1690,1615,1556,1538；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

(4.53 2H, t, J=5.1Hz), 4.87-5.03 (1H, brs), 7.23 (1H, dd, J=8.0Hz, J=8.0Hz),

7.52-7.58 (2H, m) chloro- 1, the 2- benzo isoxazole hydrochlorates of (b) 3- (2- amino ethoxies) -7-

According to embodiment 1 (f) similar the method reaction and processing, the title compound is made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -7-, yield is 98%.

Fusing point：198-200 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1616,1599,1541,1516；

H NMR spectroscopy (DMSO-d₆)δppm：3.35 (2H, t, J=5.1Hz), 4.65 (2H, t, J=5.1Hz),

7.44 (1H, dd, J=8.0Hz, J=8.0Hz), 7.79 (1H, d, J=8.0Hz), 7.83 (1H, d, J=8.0Hz),

8.34 (3H, brs).

Embodiment 103- (2- amino ethoxies) pyrido [3,2-d] isoxazole hydrochlorates and 3- (2- amino ethoxies) pyrido [3,2-d] isoxazole dihydrochlorides (a) 2- chlorine apellagrin methyl esters

It is stirred at room temperature down, excessive diazomethane (diethyl ether solution) is added into 2- chlorine apellagrins (15.75g) ethyl acetate (200ml) suspension.By reactant mixture in being stirred 30 minutes at identical temperature, remove solvent under reduced pressure and residue is dissolved in ethyl acetate, add activated carbon.The mixture is filtered, is then evaporated under reduced pressure, the title compound (15.5g) is obtained.(b) 2- chloropyridines -3- carboxylics oxime is sour (carbohydroxamic acid)

In under ice cooling and stirring, sodium hydroxide solution (the 50ml solution of 7.65g sodium hydroxides) is added into hydroxylamine hydrochloride (6.75g) water (25ml) solution, the methanol solution of 2- chlorine apellagrins methyl esters (15.5g) is added into the solution under this stirring.After stirring 2.5 hours at room temperature, in pH is adjusted into 3.5 with 6N- hydrochloric acid under ice cooling.After 1 hour, through filtering the crystallization being settled out and using water, then washed with methanol-diethyl ether mixture (1: 1), obtain the title compound (11.0g).

Fusing point：179℃；

IR composes (atoleine) ν_maxcm^-1：3154,1645,1580；

H NMR spectroscopy (DMSO-d₆)δppm：7.34 (1H, dd, J=7.5Hz, J=5.0Hz),

(7.80 1H, dd, J=7.5Hz, 2.0Hz), 8.42 (1H, dd, J=5.0Hz, J=2.0Hz), 9.30 (1H, s), 11.00Hz (1H, s) (c) 3- pyridones simultaneously [3,2-d] isoxazoles

2- chloropyridine -3- carboxylics oxime sour (2.60g) is added into 10% sodium hydrate aqueous solution (26ml) and is flowed back 30 minutes.After pH is adjusted into 2.0 with 6N- hydrochloric acid under ice cooling, reactant mixture is made to stand 30 minutes at room temperature.Through filtering the crystallization that is settled out and using water, then washed with methanol-diethyl ether mixture (1: 1), obtain the title compound (1.68g).

Fusing point：258℃；

IR composes (atoleine) ν_maxcm^-1：2750-2050,1620,1600；

H NMR spectroscopy (DMSO-d₆)δppm：7.40 (1H, dd, J=8.0Hz, J=5.0Hz),

8.40-8.70 (2H, m).(d) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) pyrido [3,2-d] isoxazoles

According to embodiment 1 (e) similar the method reaction and processing, by 3- pyridones, simultaneously [title compound is made in 3,2-d] isoxazoles and 2- (N- t-butoxycarbonyl aminos) ethanol, and yield is 61%.

Fusing point：127-128℃；

IR composes (KBr) ν_maxcm^-1：3335,1716,1707,1615,1605,1537；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.54 (2H, t, J=5.1Hz), 4.85-5.05 (1H, brs), 7.31 (1H, dd, J=7.9Hz, J=4.6Hz),

(8.06 1H, dd, J=7.9Hz, J=1.5Hz), 8.61 (1H, dd, J=4.6Hz, J=1.5Hz) (e) 3- (2- amino ethoxies) pyrido [3,2-d] isoxazole dihydrochlorides

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl), [title compound is made in 3,2-d] isoxazoles to pyrido, and yield is 99%.

Fusing point：204-210 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1606,1538,1508；

H NMR spectroscopy (DMSO-d₆)δppm：3.35 (2H, td, J=5.1Hz, J=5.1Hz),

4.65 (2H, t, J=5.1Hz), 7.54 (1H, dd, J=7.9Hz, J=4.6Hz),

8.34 (1H, dd, J=7.9Hz, J=1.5Hz), 8.34 (3H, brs),

8.70 (1H, dd, J=4.6Hz, J=1.5Hz).(f) 3- (2- amino ethoxies) pyrido [3,2-d] isoxazole hydrochlorates

In under ice cooling and stirring, to 3- (2- amino ethoxies) pyrido [3,2-d] isoxazole dihydrochloride water (10ml) solution in add 1N sodium hydrate aqueous solutions (16ml), then by mixture at identical temperature stir 5 minutes.Reactant mixture is evaporated under reduced pressure, through being recrystallized in methanol-water mixtures (1: 1), title compound described in colorless crystals (3.2g, 94%) is obtained.

Fusing point：210-213 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3012,3003,2968,2899,2845,2803,2752,

1636,1615,1606,1538,1509；

7.54 (1H, dd, J=7.9Hz, J=4.6Hz), 8.34 (1H, dd, J=7.9Hz, J=1.5Hz),

8.36 (3H, brs), 8.70 (1H, dd, J=4.6Hz, J=1.5Hz)

Chloro- 1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 113- (2- amino ethoxies) -6- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -6-

According to embodiment 1 (e) similar the method reaction and processing, the title compound is made by chloro- 1, the 2- benzoisoxazoles of 3- hydroxyls -6- and 2- (N- t-butoxycarbonyl aminos) ethanol, yield is 60%.

Fusing point：95-96℃；

IR composes (KBr) ν_maxcm^-1：3398,1698,1614,1541,1519；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.64 (2H, q, J=5.1Hz),

4.50 (2H, t, J=5.1Hz), 4.88-5.02 (1H, brs), 7.27 (1H, dd, J=8.4Hz, J=1.5Hz),

7.47 (1H, d, J=1.5Hz), 7.55 chloro- 1, the 2- benzo isoxazole hydrochlorates of (1H, d, J=8.4Hz) (b) 3- (2- amino ethoxies) -6-

According to embodiment 1 (f) similar the method reaction and processing, the title compound is made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -6-, yield is 97%.

Fusing point：198-202 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1612,1537；

H NMR spectroscopy (DMSO-d₆)δppm：3.34 (2H, t, J=5.1Hz), 4.62 (2H, t, J=5.1Hz),

7.48 (1H, dd, J=8.4Hz, J=1.5Hz), 7.81 (1H, d, J=8.4Hz), 7.92 (1H, d, J=1.5Hz),

8.36 (3H, brs)

Chloro- 1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 123- (2- amino ethoxies) -5,7- bis- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -5,7- bis-

According to embodiment 1 (e) similar the method reaction and processing, the title compound is made by chloro- 1, the 2- benzoisoxazoles of 3- hydroxyls -5,7- bis- and 2- (N- t-butoxycarbonyl aminos) ethanol, yield is 68%.

Fusing point：94-95℃；

IR composes (KBr) ν_maxcm^-1：3359,1678,1542,1524；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.64 (2H, q, J=5.1Hz),

(4.51 2H, t, J=5.1Hz), 4.85-5.00 (1H, brs), 7.54 chloro- 1, the 2- benzo isoxazole hydrochlorates of (2H, d, J=1.0Hz) (b) 3- (2- amino ethoxies) -5,7- bis-

According to embodiment 1 (f) similar the method reaction and processing, the title compound is made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -5,7- bis-, yield is 92%.

Fusing point：198-203 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1600,1541,1514；

H NMR spectroscopy (DMSO-d₆)δppm：3.34 (2H, t, J=5.1Hz), 4.63 (2H, t, J=5.1Hz),

(3H, the brs) of 7.91 (1H, d, J=2.0Hz), 8.03 (1H, d, J=2.0Hz), 8.31

Embodiment 133- (2- amino ethoxies) -7- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methyl isophthalic acids, 2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, by 3- hydroxyl -7- methyl isophthalic acids, the title compound is made in 2- benzoisoxazoles and 2- (N- t-butoxycarbonyl aminos) ethanol, and yield is 66%.

Fusing point：54-55℃；

IR composes (KBr) ν_maxcm^-1：3332,1713,1699,1615,1539,1506；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.51 (3H, s) .3.65 (2H, q, J=5.1Hz),

4.51 (2H, t, J=5.1Hz), 4.90-5.06 (1H, brs), 7.15-7.47 (3H, m) (b) 3- (2- amino ethoxies) -7- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methyl isophthalic acids, the title compound is made in 2- benzoisoxazoles, and yield is 96%.

Fusing point：195-197 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1614,1545,1520,1505；

H NMR spectroscopy (DMSO-d₆)δppm：2.47 (3H, s), 3.34 (2H, t, J=5.1Hz),

4.62 (2H, t, J=5.1Hz), 7.28-7.61 (3H, m).

Embodiment 143- (2- amino ethoxies) -6- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -6- methyl isophthalic acids, 2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, by 3- hydroxyl -6- methyl isophthalic acids, the title compound is made in 2- benzoisoxazoles and 2- (N- t-butoxycarbonyl aminos) ethanol, and yield is 64%.

Fusing point：128-129℃；

IR composes (KBr) ν_maxcm^-1：3331,1718,1708,1629,1613,1534；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.50 (3H, s), 3.65 (2H, q, J=5.1Hz),

4.49 (2H, t, J=5.1Hz), 4.90-5.05 (1H, brs), 7.10 (1H, d, J=8.0Hz), 7.23 (1H, s),

7.50 (1H, d, J=8.0Hz) (b) 3- (2- amino ethoxies) -6- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -6- methyl isophthalic acids, the title compound is made in 2- benzoisoxazoles, and yield is 92%.

Fusing point：207-212 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1618,1600,1533；

H NMR spectroscopy (DMSO-d₆)δppm：2.48 (3H, s), 3.33 (2H, t, J=5.1Hz),

4.59 (2H, t, J=5.1Hz), 7.23 (1H, d, J=8.0Hz), 7.46 (1H, s), 7.65 (1H, d, J=8.0Hz),

8.33 (3H, brs)

Bromo- 1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 153- (2- amino ethoxies) -5- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) bromo- 1,2- benzoisoxazoles of -5-

According to embodiment 1 (e) similar the method reaction and processing, the title compound is made by bromo- 1, the 2- benzoisoxazoles of 3- hydroxyls -5- and 2- (N- t-butoxycarbonyl aminos) ethanol, yield is 67%.

Fusing point：123-124℃；

IR composes (KBr) ν_maxcm^-1：3313,1699,1683,1611,1545；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.64 (2H, q, J=5.1Hz),

4.50 (2H, t, J=5.1Hz), 4.85-5.00 (1H, brs), 7.33 (1H, d, J=8.9Hz),

7.62 (1H, dd, J=8.9Hz, J=1.9Hz), 7.80 bromo- 1, the 2- benzo isoxazole hydrochlorates of (1H, d, J=1.9Hz) (b) 3- (2- amino ethoxies) -5-

According to embodiment 1 (f) similar the method reaction and processing, the title compound is made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) bromo- 1,2- benzoisoxazoles of -5-, yield is 95%.

Fusing point：220-224 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1611,1535,1516；

H NMR spectroscopy (DMSO-d₆)δppm：3.38 (2H, t, J=5.1Hz), 4.61 (2H, t, J=5.1Hz),

7.67 (1H, d, J=8.9Hz), 7.83 (1H, dd, J=8.9Hz, J=1.9Hz), 8.02 (1H, d, J=1.9Hz),

8.25 (3H, brs)

Embodiment 163, chloro- 1, the 2- benzoisoxazoles of 5- bis-

With being stirred at room temperature in lower 1 hour, pyridine (48ml) is added dropwise into phosphoryl chloride phosphorus oxychloride (80ml) suspension of 5- chloro-3-hydroxyls -1,2- benzoisoxazole (100g), then mixture flows back 5 hours.Reactant mixture is added in frozen water (500ml) and is extracted with ethyl acetate, the extract of merging is dried with anhydrous magnesium sulfate.Remove solvent under reduced pressure, residue is recrystallized in petroleum ether, obtain title compound described in colourless needles (102g, 92%).

Fusing point：43-44℃；

IR composes (KBr) ν_maxcm^-1：1648,1419,1285；

H NMR spectroscopy (CDCl₃)δppm：7.59 (2H, d, J=1.5Hz), 7.70 (1H, brs).

The fluoro- 4- methyl isophthalic acids of embodiment 173- (2- amino ethoxies) -5-, 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) fluoro- 1,2- benzoisoxazoles of -5-

In at 5 DEG C into triphenylphosphine (0.87g) tetrahydrofuran (20ml) solution add diethyl azodiformate (0.57g) and by mixture at identical temperature stir 15 minutes.Then fluoro- 3- hydroxyls -1, the 2- benzoisoxazoles (0.46g) of 5- are added and by mixture in being stirred 15 minutes at identical temperature, is subsequently added N- tertiary butyloxycarbonyls ethylethanolamine (0.48g) and stirs 24 hours at room temperature.Remove solvent under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (9/1), obtains title compound described in colorless powder (0.53g, 60%).

Fusing point：104-105℃；

IR composes (KBr) ν_maxcm^-1：3338,1707,1623,1543,1534,1504；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.64 (2H, q, J=5.1Hz),

4.50 (2H, t, J=5.1Hz), 4.95 (1H, brs), 7.22-7.42 (3H, m) .b) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) fluoro- 4- methyl isophthalic acids of -5-, 2- benzoisoxazoles

In under -70 DEG C of blanket of nitrogen and stirring, to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- fluoro- 1, lithium diisopropylamide (1.1ml is added dropwise in tetrahydrofuran (10ml) solution of 2- benzoisoxazoles (0.27g), 1.5M cyclohexane solutions), add before iodomethane (0.13g), by mixture in stirring 15 minutes at identical temperature.After being stirred 15 minutes at -70 DEG C, temperature is made to rise to 0 DEG C.Reactant mixture is poured into frozen water (40ml), (each 40ml) twice is extracted with ethyl acetate, the extract anhydrous magnesium sulfate of merging is dried and filtered.Remove solvent under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (9/1), obtains title compound described in colorless powder (0.22g, yield 94%).

Fusing point：124-127℃；

IR composes (KBr) ν_maxcm^-1：3353,1688,1539,1505；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 2.50 (3H, d, J=2.0Hz),

3.65 (2H, q, J=5.1Hz), 4.49 (2H, t, J=5.1Hz), 4.88 (1H, brs), 7.15-7.30 (2H, m) the fluoro- 4- methyl isophthalic acids of (c) 3- (2- amino ethoxies) -5-, 2- benzo isoxazole hydrochlorates

By 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) the fluoro- 4- methyl isophthalic acids of -5-, 2- benzoisoxazoles (0.15g) are dissolved in 4N hydrochloric acid/dioxane solutions (1.4ml) and stirred 15 minutes.Reactant mixture is evaporated under reduced pressure and filtered the crystallization being settled out.With ethyl acetate (3ml) wash crystallization, title compound described in colorless powder (0.13g, yield 98%) is obtained.

Fusing point：213-215 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1630,1583,1537,1505；

H NMR spectroscopy (DMSO-d₆)δppm：2.51 (3H, d, J=2.0Hz), 3.34 (2H, q, J=5.1Hz),

4.62 (2H, t, J=5.1Hz), 7.45-7.55 (2H, m), 8.33 (3H, brs)

Fluoro- 1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 183- (2- amino ethoxies) -4- carbamoyls -5- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) fluoro- 1,2- benzoisoxazoles of -4- carboxyls -5-

In under -70 DEG C of blanket of nitrogen, to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- fluoro- 1, lithium diisopropylamide (1.4ml, 1.5M cyclohexane solution) is added dropwise in tetrahydrofuran (20ml) solution of 2- benzoisoxazoles (0.30g) and by reactant mixture in stirring 15 minutes at identical temperature.It is passed through carbon dioxide gas 10 minutes and makes temperature rise to 0 DEG C.Reactant mixture is poured into frozen water (40ml) and washed twice (each 40ml) with ether.Water layer is separated, after pH is adjusted into 4 with potassium dihydrogen phosphate, is extracted with ethyl acetate (each 40ml) twice.The extract of merging is dried with anhydrous magnesium sulfate, is filtered and is removed solvent under reduced pressure, obtains title compound described in colorless oil (0.31g, yield 90%).

IR composes (KBr) ν_maxcm^-1：3474,3358,3326,3194,1683,1673,1611,

1538,1503；

H NMR spectroscopy (CDCl₃)δppm：1.38 (9H, s), 3.62 (2H, q, J=5.1Hz),

4.52 (2H, t, J=5.1Hz), 5.27 (1H, brs), 6.04 (1H, brs), 6.40 (1H, brs),

(7.34 1H, t, J=9.1Hz); 7.48 (1H, dd, J=9.1Hz; J=3.6Hz) (b) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) fluoro- 1, the 2- benzoisoxazoles of -4- carbamoyls -5-

Under 5 DEG C are stirred, to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carboxyls -5- fluoro- 1, chloro-carbonic acid tertiary butyl ester (0.14g) and triethylamine (0.11g) are added in tetrahydrofuran (20ml) solution of 2- benzoisoxazoles (0.31g), is then stirred the mixture for 15 minutes.The tetrahydrofuran solution (saturation, 5ml at room temperature) of ammonia saturation is added into reactant mixture and is stirred 15 minutes.Reactant mixture is poured into frozen water (40ml), (twice, each 40ml) is extracted with ether, the extract anhydrous magnesium sulfate of merging is dried and filtered.Remove solvent under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (4/1), obtains title compound described in colorless powder (0.24g, yield 78%).

Fusing point：63-65℃；

IR composes (KBr) ν_maxcm^-1：3473,3359,3327,3195,1683,1673,1612,

1538,1503；

H NMR spectroscopy (CDCl₃)δppm：1.38 (9H, s), 3.62 (2H, q, J=5.1Hz),

4.52 (2H, t, J=5.1Hz), 5.27 (1H, brs), 6.04 (1H, brs), 6.40 (1H, brs),

7.34 (1H, t, J=9.5Hz), 7.48 fluoro- 1, the 2- benzo isoxazole hydrochlorates of (1H, dd, J=9.5Hz, J=3.6Hz) (c) 3- (2- amino ethoxies) -4- carbamoyls -5-

According to embodiment 17 (c) similar the method reaction and processing; by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carbamoyls -5- fluoro- 1; title compound (20mg, 99%) described in colorless powder is made in 2- benzoisoxazoles (25mg) and 4N hydrochloric acid/dioxane solutions (0.2ml).

Fusing point：201-205 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3382,3400-2400,1656,1605,1590,1543；

H NMR spectroscopy (DMSO-d₆)δppm：3.30 (2H, t, J=5.1Hz), 4.62 (2H, t, J=5.1Hz),

7.63 (1H, t, J=9.5Hz), 7.77 (1H, dd, J=9.5Hz, J=3.6Hz), 7.86 (1H, brs),

8.19 (4H, brs)

Fluoro- 1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 193- (2- amino ethoxies) -4- cyano group -5- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) fluoro- 1,2- benzoisoxazoles of -4- cyano group -5-

Under 5 DEG C are stirred; to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carbamoyls -5- fluoro- 1; phosphoryl chloride phosphorus oxychloride (0.12g) is added in dimethylformamide (2.0ml) solution of 2- benzoisoxazoles (0.25g), then by mixture in stirring 15 minutes at identical temperature.Reactant mixture is poured into frozen water (20ml), (twice, each 20ml) is extracted with ethyl acetate, the extract anhydrous magnesium sulfate of merging is dried and filtered.Remove solvent under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (4/1), obtains title compound described in colorless powder (0.20g, yield 87%).

Fusing point：116-117℃；

IR composes (KBr) ν_maxcm^-1：3368,2240,1702,1532,1507；

MR composes (CDCl₃)δppm：1.45 (9H, s), 3.67 (2H, q, J=5.1Hz),

4.54 (2H, t, J=5.1Hz), 5.05 (1H, brs), 7.43 (1H, t, J=9.5Hz),

7.68 fluoro- 1, the 2- benzo isoxazole hydrochlorates of (1H, dd, J=9.5Hz, J=3.6Hz) (b) 3- (2- amino ethoxies) -4- cyano group -5-

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- cyano group -5- fluoro- 1, title compound (0.12g, yield 96%) described in colorless powder is made in 2- benzoisoxazoles (0.17g) and 4N hydrochloric acid/dioxane solutions (1.3ml).

Fusing point：190-193 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,2240,1607,1541,1505；

H NMR spectroscopy (DMSO-d₆)δppm：3.34 (2H, t, J=5.2Hz), 4.72 (2H, t, J=5.2Hz),

(3H, the brs) of 7.91 (1H, t, J=9.5Hz), 8.19 (1H, dd, J=9.5Hz, J=3.7Hz), 8.30

The fluoro- 4- methoxycarbonyl groups -1 of embodiment 203- (2- amino ethoxies) -5-, 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) fluoro- 4- methoxycarbonyl groups -1,2- benzoisoxazoles of -5-

In at 5 DEG C to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carboxyls -5- fluoro- 1, diazomethane/diethyl ether solution is added in ether (20ml) solution of 2- benzoisoxazoles (0.31g) until reactant mixture yellowing, is then stirred the mixture for 15 minutes.Reactant mixture is evaporated under reduced pressure, title compound described in oily (0.32g, yield 100%) is obtained.

IR composes (KBr) ν_maxcm^-1：3457,1733,1713,1541,1504；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.62 (2H, q, J=5.1Hz), 4.01 (3H, s),

4.49 (2H, t, J=5.1Hz), 5.08 (1H, brs), 7.35 (1H, t, J=9.5Hz),

7.52 fluoro- 4- methoxycarbonyl groups -1, the 2- benzo isoxazole hydrochlorates of (1H, dd, J=9.5Hz, J=3.6Hz) (b) 3- (2- amino ethoxies) -5-

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) the fluoro- 4- methoxycarbonyl groups -1 of -5-, title compound (0.15g, yield 97%) described in colorless powder is made in 2- benzoisoxazoles (0.18g) and 4N- hydrochloric acid/dioxane solutions (1.3ml).

Fusing point：168-170 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1729,1584,1539,1501；

H NMR spectroscopy (DMSO-d₆)δppm：3.31 (2H, t, J=5.1Hz), 3.96 (3H, s),

4.62 (2H, t, J=5.1Hz), 7.73 (2H, t, J=9.5Hz), 7.96 (2H, dd, J=9.5Hz, J=3.6Hz),

8.23 (3H, brs)

Fluoro- 4- methyl mercapto -1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 213- (2- amino ethoxies) -5- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) fluoro- 4- methyl mercaptos -1,2- benzoisoxazoles of -5-

In under -70 DEG C of blanket of nitrogen and stirring, to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- fluoro- 1, lithium diisopropylamide (1.50ml is added dropwise in tetrahydrofuran (20ml) solution of 2- benzoisoxazoles (0.30g), 1.5M cyclohexane solutions), after being stirred 15 minutes at identical temperature, dimethyl disulphide (0.21g) is added.By reactant mixture in being stirred 15 minutes at -70 DEG C, temperature is then made to rise to 0 DEG C.Reactant mixture is poured into frozen water (40ml), (twice, each 40ml) is extracted with ethyl acetate, the extract of merging is dried with anhydrous magnesium sulfate.After filtering, solvent is removed under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (9/1), obtains title compound described in colorless powder (0.32g, yield 94%).

Fusing point：91-92℃；

IR composes (KBr) ν_maxcm^-1：3335,1694,1618,1540；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 2.60 (3H, d, J=2.1Hz),

3.67 (2H, q, J=5.1Hz), 4.50 (2H, t, J=5.1Hz), 5.04 (1H, brs), 7.20-7.30 (2H, m) fluoro- 4- methyl mercaptos -1, the 2- benzo isoxazole hydrochlorates of (b) 3- (2- amino ethoxies) -5-

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) the fluoro- 4- methyl mercaptos -1 of -5-, title compound (0.15g, yield 99%) described in colorless powder is made in 2- benzoisoxazoles (0.18g) and 4N hydrochloric acid/dioxane solutions (1.3ml).

Fusing point：183-185 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3400-2400,1617,1592,1535；

H NMR spectroscopy (DMSO-d₆)δppm：2.57 (3H, d, J=1.4Hz), 3.35 (3H, t, J=5.1Hz),

4.64 (2H, t, J=5.1Hz), 7.59 (1H, t, J=9.5Hz), 7.63 (1H, dd, J=9.5Hz, J=3.6Hz),

8.24 (3H, brs) embodiments 223- (2- amino ethoxies) -4- methoxycarbonyl groups -1,2- benzo isoxazole hydrochlorates and 3- (2- amino ethoxies) -7- methoxycarbonyl groups -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1,2- benzoisoxazoles

Under 5 DEG C are stirred, diethyl azodiformate (0.63g) is added into triphenylphosphine (0.95g) tetrahydrofuran (20ml) solution, then in stirring 15 minutes at identical temperature.3- hydroxyls -1,2- benzoisoxazole (0.45g) is added into reactant mixture and is stirred 15 minutes, N- tertiary butyloxycarbonyls ethylethanolamine (0.53g) is then added and stirs mixture at room temperature 24 hours.Remove solvent under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (9/1), obtains the title compound (0.63g, 68%).

Fusing point：106-107℃；

IR composes (KBr) ν_maxcm^-1：3326,1716,1707,1615,1536；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.51 (2H, t, J=5.1Hz), 4.90-5.05 (1H, brs), 7.26-7.66 (4H, m) (b) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- methoxycarbonyl groups -1,2- benzoisoxazoles and 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methoxycarbonyl group -1,2- benzoisoxazoles

In under -70 DEG C of blanket of nitrogen and stirring, to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1, butyl lithium (1.40ml is added dropwise in tetrahydrofuran (30ml) solution of 2- benzoisoxazoles (0.28g), 1.6M hexane solutions), and by mixture in stirring 15 minutes at identical temperature.Carbon dioxide gas 10 minutes is passed through into reactant mixture and makes temperature rise to 0 DEG C.Reactant mixture is poured into frozen water (40ml) and extracted with ether (twice, each 40ml).Water layer is separated, after pH is adjusted into 4 with potassium dihydrogen phosphate, is extracted with ethyl acetate (twice, each 40ml).The extract anhydrous magnesium sulfate of merging is dried and filtered.Remove solvent under reduced pressure, obtain 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) 4- methoxycarbonyl groups -1,2- benzoisoxazoles and 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methoxycarbonyl groups -1,2- benzoisoxazole colorless oils mixture (0.31g, 92%).

Gained mixture is dissolved in ether (15ml), is then cooled to 5 DEG C, diazomethane/diethyl ether solution is added dropwise up to reactant mixture yellowing, then by mixture in stirring 15 minutes at identical temperature.Remove solvent under reduced pressure, residue is through silica gel chromatography, make eluant, eluent with cyclohexane/ethyl acetate (4/1), respectively obtain title compound 3- described in colorless powder (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- methoxycarbonyl groups -1,2- benzoisoxazoles (0.15g, 45%) with 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methoxycarbonyl groups -1,2- benzoisoxazole (0.08g, 24%).

The relevant data of 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- methoxycarbonyl group -1,2- benzoisoxazoles.

Fusing point：95-96℃；

IR composes (KBr) ν_maxcm^-1：3397,1705,1601,1533,1524,1503；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.66 (2H, q, J=5.1Hz), 3.99 (3H, s),

4.51 (2H, t, J=5.1Hz), 5.29 (1H, brs), 7.55-7.65 (2H, m), 7.85 (1H, d, J=7.5Hz)

The relevant data of 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methoxycarbonyl group -1,2- benzoisoxazoles.

Fusing point：90-91℃；

IR composes (KBr) ν_maxcm^-1：3387,1718,1693,1620,1610,1552,1525；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.66 (2H, q, J=5.1Hz), 4.03 (3H, s),

4.54 (2H, t, J=5.1Hz), 4.96 (1H, brs), 7.37 (1H, t, J=8.1Hz), 7.85 (1H, d, J=8.1Hz),

8.23 (3H, d, J=8.0Hz) (c) 3- (2- amino ethoxies) -4- methoxycarbonyl group -1,2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- methoxycarbonyl groups -1, title compound (0.08g, yield 100%) described in colorless powder is made in 2- benzoisoxazoles (0.10g) and 4N hydrochloric acid/dioxane solutions (1.0ml).

Fusing point：169-172 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1718,1601,1525,1499；

H NMR spectroscopy (DMSO-d₆)δppm：3.34 (2H, t, J=5.1Hz), 3.93 (3H, s),

4.62 (2H, t, J=5.1Hz), 7.75-7.85 (2H, m), 7.95 (1H, d, J=8.1Hz), 8.23 (3H, brs) (d) 3- (2- amino ethoxies) -7- methoxycarbonyl group -1,2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methoxycarbonyl groups -1, title compound (0.06g, yield 100%) described in colorless powder is made in 2- benzoisoxazoles (0.08g) and 4N- hydrochloric acid/dioxane solutions (1.0ml).

Fusing point：211-213 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1730,1719,1618,1608,1550,1502；

H NMR spectroscopy (DMSO-d₆)δppm：3.36 (2H, t, J=5.1Hz), 3.95 (3H, s),

4.65 (2H, t, J=5.1Hz), 7.56 (1H, t, J=8.0Hz), 8.10 (1H, d, J=8.1Hz),

8.23 (1H, d, J=8.1Hz), 8.30 (3H, brs)

Embodiment 233- (2- amino ethoxies) -4- carbamoyls -1; 2- benzo isoxazole hydrochlorates and 3- (2- amino ethoxies) -7- carbamoyls -1; 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carbamoyls -1; 2- benzoisoxazoles and 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- carbamoyl -1,2- benzoisoxazoles

In under -70 DEG C of blanket of nitrogen and stirring, to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1, butyl lithium (3.0ml is added dropwise in tetrahydrofuran (30ml) solution of 2- benzoisoxazoles (0.55g), 1.6M hexane solutions), and by mixture in stirring 15 minutes at identical temperature.Carbon dioxide gas 10 minutes is passed through into reactant mixture and makes temperature rise to 0 DEG C.Reactant mixture is poured into frozen water (40ml) and extracted with ether (twice, each 40ml).Water layer is separated, after pH is adjusted into 4 with potassium dihydrogen phosphate, is extracted with ethyl acetate (twice, each 40ml).The extract of merging is dried with anhydrous magnesium sulfate, filter and remove solvent under reduced pressure, obtain 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carboxyls -1,2- benzoisoxazoles and 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- carboxyl -1,2- benzoisoxazole colorless oil mixtures (0.48g).

Then, gained mixture is dissolved in tetrahydrofuran (30ml), under 5 DEG C are stirred, isobutyl chloroformate (0.23g) and triethylamine (0.18g) are added into this solution, then stir the mixture for 15 minutes, it is subsequently added the tetrahydrofuran solution (saturation, 5ml at room temperature) of ammonia-saturation and stirs 15 minutes.Reactant mixture is poured into frozen water (40ml), (twice, each 40ml) is extracted with ethyl acetate, the extract anhydrous magnesium sulfate of merging is dried and filtered.Remove solvent under reduced pressure; residue is through silica gel chromatography; make eluant, eluent with cyclohexane/ethyl acetate (4/1); respectively obtain colorless powder 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carbamoyls -1; 2- benzoisoxazoles (0.30g; 47%) with 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- carbamoyls -1,2- benzoisoxazole (0.17g, 26%).

The relevant data of 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carbamoyl -1,2- benzoisoxazoles.

Fusing point：119-120℃；

IR composes (KBr) ν_maxcm^-1：3488,3443,3358,3196,1688,1663,1610,

1592,1533；

H NMR spectroscopy (CDCl₃)δppm：1.42 (9H, s), 3.70 (2H, q, J=5.1Hz),

4.62 (2H, t, J=5.1Hz), 4.93 (1H, brs), 5.91 (1H, brs), 7.60-7.70 (2H, m),

(7.79 1H, brs), 8.14 (1H, d, J=7.0Hz)

The relevant data of 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- carbamoyl -1,2- benzoisoxazoles.

Fusing point：151-153℃；

IR composes (KBr) ν_maxcm^-1：3463,3396,33 53,3304,3232,3182,1716,

1680,1618,1544；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.67 (2H, q, J=5.1Hz),

4.54 (2H, t, J=5.1Hz), 4.97 (1H, brs), 5.95 (1H, brs), 7.14 (1H, brs),

(7.44 1H, t, J=7.0Hz), 7.83 (1H, d, J=7.0Hz), 8.35 (1H, d, J=7.0Hz) (b) 3- (2- amino ethoxies) -4- carbamoyl -1,2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing; by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carbamoyls -1; title compound (0.08g, yield 100%) described in colorless powder is made in 2- benzoisoxazoles (0.10g) and 4N- hydrochloric acid/dioxane solutions (1.0ml).

Fusing point：210-213 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3383,3300-2400,1656,1605,1590,1543；

H NMR spectroscopy (DMSO-d₆)δppm：3.57 (2H, t, J=5.1Hz), 4.64 (2H, t, J=5.1Hz),

7.58 (1H, d, J=7.0Hz), 7.71 (1H, brs), 7.73 (1H, dd, J=9.0Hz, J=7.0Hz),

7.79 (1H, d, J=9.0Hz), 7.99 (1H, brs), 8.21 (3H, brs) (c) 3- (2- amino ethoxies) -7- carbamoyl -1,2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing; by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- carbamoyls -1; title compound (0.04g, yield 100%) described in colorless powder is made in 2- benzoisoxazoles (0.05g) and 4N- hydrochloric acid/dioxane solutions (1.0ml).

Fusing point：227-230 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3461,3180,3300-2400,1675,1618,1596,

1547；

H NMR spectroscopy (DMSO-d₆)δppm：3.34 (2H, t, J=5.1Hz), 4.65 (2H, t, J=5.1Hz),

7.50 (1H, t, J=7.0Hz), 7.77 (1H, brs), 7.83 (1H, brs), 7.95 (1H, d, J=7.0Hz),

8.05 (1H, d, J=7.0Hz), 8.31 (3H, brs)

Embodiment 243- (2- amino ethoxies) -4- cyano group -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- cyano group -1,2- benzoisoxazoles

Under 5 DEG C are stirred; to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carbamoyls -1; phosphoryl chloride phosphorus oxychloride (0.9g) is added in diethylformamide (1.5ml) solution of 2- benzoisoxazoles (0.15g), then by mixture in stirring 15 minutes at identical temperature.Reactant mixture is poured into frozen water (20ml), (twice, each 20ml) is extracted with ethyl acetate, the extract of merging is dried with anhydrous magnesium sulfate.After filtering, solvent is removed under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (4/1), obtains title compound described in colorless powder (0.13g, 93%).

Fusing point：116-117℃；

IR composes (KBr) ν_maxcm^-1：3370,2232,1701,1601,1530；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 3.69 (2H, q, J=5.1Hz),

4.55 (2H, t, J=5.1Hz), 5.08 (1H, brs), 7.60-7.75 (3H, m) (b) 3- (2- amino ethoxies) -4- cyano group -1,2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- cyano group -1, title compound (0.08g, yield 100%) described in colorless powder is made in 2- benzoisoxazoles (0.10g) and 4N- hydrochloric acid/dioxane solutions (1.0ml).

Fusing point：210-213 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3400-2400,2234,1601,1538；

H NMR spectroscopy (DMSO-d₆)δppm：3.35 (2H, t, J=5.1Hz), 4.72 (2H, t, J=5.1Hz),

(3H, the brs) of 7.87 (1H, t, J=8.1Hz), 7.98 (1H, d, J=8.1Hz), 8.09 (1H, d, J=8.1Hz), 8.26

Embodiment 253- (2- amino ethoxies) -7- cyano group -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- cyano group -1,2- benzoisoxazoles

Under 5 DEG C are stirred; to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- carbamoyls -1; phosphoryl chloride phosphorus oxychloride (0.06g) is added in dimethylformamide (1.0ml) solution of 2- benzoisoxazoles (0.10g), then by mixture in stirring 15 minutes at identical temperature.Reactant mixture is poured into frozen water (20ml), (twice, each 20ml) is extracted with ethyl acetate, the extract of merging is dried with anhydrous magnesium sulfate.After filtering, solvent is removed under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (4/1), obtains title compound described in colorless powder (0.09g, 90%).

Fusing point：91-92℃；

IR composes (KBr) ν_maxcm^-1：3437,3349,3316,2238,1719,1701,1688,

1621,1607,1546,1528；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 3.66 (2H, q, J=5.1Hz),

4.54 (2H, t, J=5.1Hz), 4.92 (1H, brs), 7.40 (1H, t, J=8.0Hz), 7.86 (1H, d, J=8.0Hz),

7.90 (1H, d, J=8.0Hz) (b) 3- (2- amino ethoxies) -7- cyano group -1,2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- cyano group -1, title compound (0.05g, yield 100%) described in colorless powder is made in 2- benzoisoxazoles (0.07g) and 4N- hydrochloric acid/dioxanes molten (1.0ml).

Fusing point：205-208 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3241,3400-2400,2239,1623,1607,1547；

H NMR spectroscopy (DMSO-d₆)δppm：3.36 (2H, t, J=5.1Hz), 4.67 (2H, t, J=5.1Hz),

(3H, the brs) of 7.61 (1H, t, J=8.1Hz), 8.18 (1H, d, J=8.1Hz), 8.26 (1H, d, J=8.1Hz), 8.34

Fluoro- fluoro- 1, the 2- benzoisoxazoles of the chloro- 5- of 1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 263- (2- aminoethanethios) -5-

Phosphoryl chloride phosphorus oxychloride (0.89g) is added into pyridine (0.53ml) solution of the fluoro- 3- hydoxyisoxazoles (1.0g) of 5- and mixture flows back 8 hours.Reactant mixture is poured into frozen water, is extracted with ethyl acetate, the extract of merging is washed with saturated brine and dried with anhydrous magnesium sulfate.After filtering, solvent is removed under reduced pressure, residue obtains title compound described in colorless oil (0.85g, 77%) through silica gel chromatography.(b) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) fluoro- 1, the 2- benzoisoxazoles of -5-

Under blanket of nitrogen stirring, to the chloro- 5- of 3- fluoro- 1,2- t-butoxycarbonyl aminos ethyl mercaptan (0.86g) and potassium carbonate (0.67g) are added in dimethylformamide (8ml) solution of 2- benzoisoxazoles (0.83g), then by mixture in stirring 3 hours at 80 DEG C.Reactant mixture is poured into frozen water, is extracted with ethyl acetate, the extract of merging is dried with salt water washing and with anhydrous magnesium sulfate.After filtering, solvent is removed under reduced pressure, residue obtains title compound described in colorless powder (1.21g, 80%) through silica gel chromatography.

H NMR spectroscopy (CDCl₃)δppm：1.44 (9H, s), 3.41 (2H, t, J=6.2Hz),

3.58 (2H, td, J=6.2Hz, J=6.2Hz), 4.98 (1H, brs), 7.21-7.51 (3H, m).(c) fluoro- 1, the 2- benzo isoxazole hydrochlorates of 3- (2- aminoethanethios) -5-

Under 5 DEG C are stirred, to 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- fluoro- 1,2- benzoisoxazoles (add 4N- hydrochloric acid/dioxane solutions (0.8ml), then stirred mixture at room temperature 30 minutes in 0.20g) dioxanes (2ml) solution.After the completion of reaction, solvent is removed under reduced pressure, residue is recrystallized in ethanol and ethyl acetate, obtains title compound described in colourless needles (0.14g).

Fusing point：202-206 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：2992,2955,2915,1594,1511,1493；

H NMR spectroscopy (DMSO-d₆)δppm：3.25 (2H, t, J=7.1Hz), 3.53 (2H, t, J=7.1Hz),

7.60-7.86 (3H, m), 8.22 (3H, brs).Chloro- 1, the 2- benzo isoxazole hydrochlorates (a) 3 of embodiment 273- (2- aminoethanethios) -7-, chloro- 1, the 2- benzoisoxazoles of 7- bis-

According to embodiment 26 (a) similar the method reaction and processing, the title compound (0.73g, 78%) is made by 7- chloro-3-hydroxyls -1,2- benzoisoxazole (0.85g).(b) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) chloro- 1, the 2- benzoisoxazoles of -7-

According to embodiment 26 (b) similar the method reaction and processing, the title compound (0.22g, 63%) is made by chloro- 1, the 2- benzoisoxazoles (0.20g) of 3,7- bis-.

H NMR spectroscopy (CDCl₃)δppm：1.43 (9Hs), 3.42 (2H, t, J=6.2Hz),

3.60 (2H, td, J=6.2Hz, J=6.2Hz), 5.01 (1H, brs), 7.24 (1H, t, J=9.1Hz),

7.48 (1H, d, J=9.1Hz), 7.56 chloro- 1, the 2- benzo isoxazole hydrochlorates of (1H, d, J=9.1Hz) (c) 3- (2- aminoethanethios) -7-

According to embodiment 26 (c) similar the method reaction and processing, title compound (the 0.12g is made by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) chloro- 1,2- benzoisoxazoles (0.15g) of -7-；It is quantitative).

Fusing point：196-201 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：2971,2909,1592,1502,1492；

H NMR spectroscopy (DMSO-d₆)δppm：3.26 (2H, t, J=7.1Hz), 3.56 (2H, t, J=7.1Hz),

(3H, the brs) of 7.45 (1H, t, J=7.9Hz), 7.79 (1H, d, J=7.9Hz), 7.86 (1H, d, J=7.9Hz), 8.20

Embodiment 283- (2- aminoethanethios) -7- methyl isophthalic acids, the chloro- 7- methyl isophthalic acids of 2- benzo isoxazole hydrochlorates (a) 3-, 2- benzoisoxazoles

According to embodiment 26 (a) similar the method reaction and processing, by 3- hydroxyl -7- methyl isophthalic acids, the title compound (0.30g, 77%) is made in 2- benzoisoxazoles (0.35g).(b) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -7- methyl isophthalic acids, 2- benzoisoxazoles

According to embodiment 26 (b) similar the method reaction and processing, by the chloro- 7- methyl isophthalic acids of 3-, the title compound (0.24g, 55%) is made in 2- benzoisoxazoles (0.24g).

H NMR spectroscopy (CDCl₃)δppm：1.43 (9H, s), 2.52 (3H, s), 3.42 (2H, t, J=6.2Hz), 3.58 (2H, td, J=6.2Hz, J=6.2Hz), 5.12 (1H, brs), 7.18 (1H, t, J=9.1Hz), 7.33 (1H, d, J=9.1Hz), 7.40 (1H, d, J=9.1Hz) (c) 3- (2- aminoethanethios) -7- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates

According to embodiment 26 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -7- methyl isophthalic acids, the title compound (0.08g, quantitative) is made in 2- benzoisoxazoles (0.10g).

Fusing point：198-203 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：2985,2913,1598,1501；

H NMR spectroscopy (DMSO-d₆)δppm：2.51 (3H, s), 3.24 (2H, t, J=7.1Hz),

3.54 (2H, t, J=7.1Hz), 7.33 (1H, t, J=7.4Hz), 7.52 (1H, d, J=7.4Hz),

7.58 (1H, d, J=7.4Hz), 8.22 (3H, brs)

Chloro- 1, the 2- benzoisoxazoles of chloro- 1, the 2- benzo isoxazole hydrochlorates (a) 3,5,7- tri- of embodiment 293- (2- aminoethanethios) -5,7- bis-

According to embodiment 26 (a) similar the method reaction and processing, the title compound (1.81g, 83%) is made by chloro-3-hydroxyl -1, the 2- benzoisoxazoles (2.00g) of 5,7- bis-.(b) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) chloro- 1, the 2- benzoisoxazoles of -5,7- bis-

According to embodiment 26 (b) similar the method reaction and processing, the title compound (0.25g, 68%) is made by 3,5,7- tri- chloro- 1,2- benzoisoxazoles (0.23g).

H NMR spectroscopy (CDCl₃)δppm：1.43 (9H, s), 3.42 (2H, t, J=6.2Hz),

3.58 (2H, td, J=6.2Hz, J=6.2Hz), 5.03 (1H, brs), 7.48 (1H, s), 7.56 (1H, s) chloro- 1, the 2- benzo isoxazole hydrochlorates of (c) 3- (2- aminoethanethios) -5,7- bis-

According to embodiment 26 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5, the title compound (0.18g, quantitative) is made in chloro- 1, the 2- benzoisoxazoles (0.22g) of 7- bis-.

Fusing point：199-202 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3003,2970,2915,1590,1480；

H NMR spectroscopy (DMSO-d₆)δppm：3.25 (1H, t, J=6.9Hz), 3.54 (2H, t, J=6.9Hz),

8.00 (1H, s), 8.06 (1H, s), 8.18 (3H, brs).

Chloro- 7- nitros -1, the 2- benzoisoxazoles of embodiment 303- (2- aminoethanethios) -7- nitro -1,2- benzo isoxazole hydrochlorates (a) 3-

According to embodiment 26 (a) similar the method reaction and processing, the title compound (0.93g, 80%) is made by 3- hydroxyl -7- nitros -1,2- benzoisoxazoles (1.05g).(b) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -7- nitro -1,2- benzoisoxazoles

According to embodiment 26 (b) similar the method reaction and processing, the title compound (0.20g, 51%) is made by chloro- 7- nitros -1, the 2- benzoisoxazoles (0.23g) of 3-.

H NMR spectroscopy (CDCl₃)δppm：1.43 (9H, s), 3.48 (2H, t, J=6.2Hz),

3.62 (2H, td, J=6.2Hz, J=6.2Hz), 4.98 (1H, brs), 7.50 (1H, t, J=9.1Hz),

7.94 (1H, d, J=9.1Hz), 8.44 (1H, d, J=9.1Hz) (c) 3- (2- aminoethanethios) -7- nitro -1,2- benzo isoxazole hydrochlorates

According to embodiment 26 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -7- nitros -1, the title compound (0.14g, quantitative) is made in 2- benzoisoxazoles (0.18g).

Fusing point：193-196 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：2990,2924,2882,1620,1589,1532,1512；

H NMR spectroscopy (DMSO-d₆)δppm：3.28 (2H, t, J=7.1Hz), 3.61 (2H, t, J=7.1Hz),

(1H, d, the J=7.9Hz) of 7.69 (1H, t, J=7.9Hz), 8.24 (3H, brs), 8.29 (1H, d, J=7.9Hz), 8.57

Chloro- 7- methoxyl groups -1, the 2- benzoisoxazoles of embodiment 313- (2- aminoethanethios) -7- methoxyl group -1,2- benzo isoxazole hydrochlorates (a) 3-

According to embodiment 26 (a) similar the method reaction and processing, the title compound (0.61g, 69%) is made by 3- hydroxyl -7- methoxyl groups -1,2- benzoisoxazoles (0.80g).(b) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -7- methoxyl group -1,2- benzoisoxazoles

According to embodiment 26 (b) similar the method reaction and processing, the title compound (0.25g, 54%) is made by chloro- 7- methoxyl groups -1, the 2- benzoisoxazoles (0.26g) of 3-.

H NMR spectroscopy (CDCl₃)δppm：1.44 (9H, s), 3.42 (2H, t, J=6.2Hz),

3.58 (2H, td, J=6.2Hz, J=6.2Hz), 4.04 (3H, s), 5.02 (1H, brs), 6.98 (1H, d, J=9.1Hz),

7.15 (1H, d, J=9.1Hz), 7.23 (1H, t, J=9.1Hz) (c) 3- (2- aminoethanethios) -7- methoxyl group -1,2- benzo isoxazole hydrochlorates

According to embodiment 26 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -7- methoxyl groups -1, the title compound (90mg, quantitative) is made in 2- benzoisoxazoles (120mg).

Fusing point：232-237 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3019,2969,2907,1619,1600,1512；

H NMR spectroscopy (DMSO-d₆)δppm：3.25 (2H, t, J=7.1Hz), 3.54 (2H, t, J=7.1Hz),

3.98 (3H, s), 7.27-7.40 (3H, m), 8.21 (3H, brs).Embodiment 323- (2- aminoethanethios) -7- amino -1,2- benzoisoxazole dihydrochlorides (a) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -7- amino -1,2- benzoisoxazoles

In under ice cooling and stirring, to 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -7- nitros -1, zinc powder (250mg) is added in 90% acetic acid aqueous solution (2ml) of 2- benzoisoxazoles (250mg), is then stirred mixture at room temperature 30 minutes.After the completion of reaction, reactant mixture is filtered through diatomite, and filtrate decompression is concentrated.Water is added into residue, is then extracted with ethyl acetate.The extract of merging is dried with salt water washing and with anhydrous magnesium sulfate.After filtering, solvent is removed under reduced pressure, residue, with ethyl acetate as eluent, obtains the title compound (230mg, quantitative) through silica gel chromatography.

H NMR spectroscopy (CDCl₃)δppm：1.43 (9H, s), 3.41 (2H, t, J=6.2Hz),

3.59 (2H, td, J=6.2Hz, J=6.2Hz), 4.08 (2H, brs), 5.02 (1H, brs),

(6.82 1H, d, J=8.7Hz), 6.96 (1H, d, J=8.7Hz), 7.12 (1H, t, J=8.7Hz) (b) 3- (2- aminoethanethios) -7- amino -1,2- benzoisoxazole dihydrochlorides

According to embodiment 26 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -7- amino -1, the title compound (120mg, quantitative) is made in 2- benzoisoxazoles (140mg).

Fusing point：157-160 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：, 3035,2969,2884,2807,2581,1631,1614,

1570,1521,1504；

H NMR spectroscopy (DMSO-d₆)δppm：3.24 (2H, t, J=7.0Hz), 3.52 (2H, t, J=7.0Hz),

(3H, the brs) of 4.05-5.35 (2H, brs), 6.88 (2H, d, J=7.9Hz), 7.12 (1H, t, J=7.9Hz), 8.23

Embodiment 333- (2- aminoethanethios) -5- methoxyl group -1,2- benzo isoxazole hydrochlorates (a) 3- chloro-5-methoxyl -1,2- benzoisoxazoles

According to embodiment 26 (a) similar the method reaction and processing, by 3- hydroxy-5-methyl Oxy-1s, the title compound (730mg, 71%) is made in 2- benzoisoxazoles (920mg).(b) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- methoxyl group -1,2- benzoisoxazoles

According to embodiment 26 (b) similar the method reaction and processing, the title compound (280mg, 61%) is made by 3- chloro-5-methoxyls -1,2- benzoisoxazole (260mg).

H NMR spectroscopy (CDCl₃)δppm：1.43 (9H, s), 3.40 (2H, t, J=6.2Hz),

3.58 (2H, td, J=6.2Hz, J=6.2Hz), 3.86 (3H, s), 5.02 (1H, brs), 6.91 (1H, s),

7.18 (1H, d, J=9.1Hz), 7.43 (1H, d, J=9.1Hz).(c) 3- (2- aminoethanethios) -5- methoxyl group -1,2- benzo isoxazole hydrochlorates

According to embodiment 26 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- methoxyl groups -1, the title compound (190mg, quantitative) is made in 2- benzoisoxazoles (240mg).

Fusing point：213-217 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：2997,2947,2883,1592,1514,1495；

H NMR spectroscopy (DMSO-d₆)δppm：3.23 (2H, t, J=7.1Hz), 3.52 (2H, t, J=7.1Hz),

3.84 (3H, s), 7.16 (1H, s), 7.32 (1H, d, J=9.1Hz), 7.69 (1H, d, J=9.1Hz),

8.17 (3H, brs)

Embodiment 343- (2- aminoethanethios) -5- methyl isophthalic acids, the chloro- 5- methyl isophthalic acids of 2- benzo isoxazole hydrochlorates (a) 3-, 2- benzoisoxazoles

According to embodiment 26 (a) similar the method reaction and processing, the title compound (0.81g, 71%) is made by 3- hydroxy-5-methyl base -1,2- benzoisoxazoles (1.02g).(b) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- methyl isophthalic acids, 2- benzoisoxazoles

According to embodiment 26 (b) similar the method reaction and processing, by the chloro- 5- methyl isophthalic acids of 3-, the title compound (90mg, 56%) is made in 2- benzoisoxazoles (90mg).

H NMR spectroscopy (CDCl₃)δppm：1.44 (9H, s), 2.46 (3H, s), 3.40 (2H, t, J=6.2Hz),

3.58 (2H, td, J=6.2Hz, J=6.2Hz), 5.02 (1H, brs), 7.38 (2H, d, J=9.1Hz), 7.42 (1H, s) (c) 3- (2- aminoethanethios) -5- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates

According to embodiment 26 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- methyl isophthalic acids, the title compound (60mg, quantitative) is made in 2- benzoisoxazoles (80mg).

Fusing point：132-135 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：2996,2919,1600,1592,1497；

H NMR spectroscopy (DMSO-d₆)δppm：2.44 (3H, s), 3.24 (2H, t, J=7.1Hz),

3.53 (2H, t ,=7.1Hz), 7.54 (1H, d, J=8.5Hz), 7.55 (1H, s), 7.65 (1H, d, J=8.5Hz),

8.21 (3H, brs)

Chloro- 5- nitros -1, the 2- benzoisoxazoles of embodiment 353- (2- aminoethanethios) -5- nitro -1,2- benzo isoxazole hydrochlorates (a) 3-

According to embodiment 26 (a) similar the method reaction and processing, the title compound (0.63g, 56%) is made by 3- hydroxyl -5- nitros -1,2- benzoisoxazoles (1.02g).(b) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- nitro -1,2- benzoisoxazoles

According to embodiment 26 (b) similar the method reaction and processing, the title compound (560mg, 58%) is made by chloro- 5- nitros -1, the 2- benzoisoxazoles (560mg) of 3-.

H NMR spectroscopy (CDCl₃)δppm：1.44 (9H, s), 3.47 (2H, t, J=6.2Hz),

3.62 (2H, td, J=6.2Hz, J=6.2Hz), 4.96 (1H, brs), 7.64 (1H, d, J=9.1Hz),

8.48 (1H, d, J=9.1Hz), 8.56 (1H, s) (c) 3- (2- aminoethanethios) -5- nitro -1,2- benzo isoxazole hydrochlorates

According to embodiment 26 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- nitros -1, the title compound (200mg, quantitative) is made in 2- benzoisoxazoles (250mg).

Fusing point：183-186 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3031,2971,2892,1619,1594,1530；

H NMR spectroscopy (DMSO-d₆)δppm：3.26 (2H, t, J=7.1Hz), 3.59 (2H, t, J=7.1Hz),

8.03 (1H, d, J=9.1Hz), 8.24 (3H, brs), 8.56 (1H, d, J=9.1Hz), 8.72 (1H, s)

Embodiment 363- (2- aminoethanethios) -5- amino -1,2- benzoisoxazole dihydrochlorides (a) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- amino -1,2- benzoisoxazoles

According to embodiment 32 (a) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- nitros -1, the title compound (140mg, quantitative) is made in 2- benzoisoxazoles (150mg).

H NMR spectroscopy (CDCl₃)δppm：1.43 (3H, s), 3.37 (2H, t, J=6.1Hz),

3.57 (2H, td, J=6.2Hz, J=6.2Hz), 3.91 (2H, brs), 5.03 (1H, brs), 6.77 (1H, s),

6.94 (1H, d, J=8.7Hz), 7.33 (1H, d, J=8.7Hz) (b) 3- (2- aminoethanethios) -5- amino -1,2- benzoisoxazole dihydrochlorides

According to embodiment 26 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- amino -1, the title compound (200mg, quantitative) is made in 2- benzoisoxazoles (200mg).

Fusing point：201-205 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3045,3021,2946,2885,1628,1582,1494；

H NMR spectroscopy (DMSO-d₆)δppm：3.26 (2H, t, J=7.0Hz), 3.35-4.85 (2H, brs),

3.55 (2H, t, J=7.0Hz), 7.54 (1H, d, J=6.5Hz), 7.56 (1H, s), 7.80 (1H, d, J=6.5Hz),

8.24 (3H, brs)

Embodiment 373- (2- amino ethoxies) -1,2- naphtho-s [2,3-e] isoxazole hydrochlorates (a) 3- hydroxyls -1,2- naphtho- [2,3-e] isoxazoles

According to embodiment 1 (a), 1 (b) and 1 (c) described similar method reaction and processing, the title compound (3.1g, 31%) is made by 3- hydroxy-2-naphthoic acids (10.0g).

IR composes (KBr) ν_maxcm^-1：3044,3001,2940,2869,2824,2746,2696,

2661,2623,1770,1645,1618,1598,1573,1521；

H NMR spectroscopy (DMSO-d₆)δppm：7.45-7.65 (2H, m), 8.01 (1H, s),

8.04 (1H, d, J=8.4Hz), 8.15 (1H, d, J=8.4Hz), 8.43 (1H, s), 12.67 (1H, brs) (b) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1,2- naphtho-s [2,3-e] isoxazoles

According to embodiment 1 (e) similar the method reaction and processing, by 3- hydroxyls -1, [title compound (0.59g, 72%) is made in 2,3-e] isoxazoles (0.46g) and 2- (N- t-butoxycarbonyl aminos) ethanol to 2- naphtho-s.

Fusing point：148-149℃；

IR composes (KBr) ν_maxcm^-1：3314,1707,1643,1545,1535；

H NMR spectroscopy (CDCl₃)δppm：1.47 (9H, s), 3.70 (2H, q, J=5.1Hz),

4.59 (2H, t, J=5.1Hz), 5.01 (1H, brs), 7.33-7.60 (2H, m), 7.81 (1H, s),

7.94 (1H, d, J=8.4Hz), 8.00 (1H, d, J=8.4Hz), 8.22 (1H, s) (c) 3- (2- amino ethoxies) -1,2- naphtho-s [2,3-e] isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1, [title compound (0.40g, 99%) is made in 2,3-e] isoxazoles (0.50g) to 2- naphtho-s.

Fusing point：207-213 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1641,1615,1545,1516,1505；

H NMR spectroscopy (DMSO-d₆)δppm：3.39 (2H, q, J=5.1Hz), 4.71 (2H, t, J=5.1Hz),

7.50-7.70 (2H, m), 8.09 (1H, d, J=8.4Hz), 8.13 (1H, s), 8.18 (1H, d, J=8.4Hz),

8.36 (3H, brs), 8.47 (1H, s)

Chloro- 1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 383- (2- aminoethanethios) -5- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) chloro- 1,2- benzoisoxazoles of -5-

According to embodiment 26 (b) similar the method reaction and processing, the title compound (0.63g, 62%) is made by chloro- 1, the 2- benzoisoxazoles (0.53g) of 3,5- bis-.

Fusing point：95-96℃；

IR composes (KBr) ν_maxcm^-1：3283,1687,1523；

H NMR spectroscopy (CDCl₃)δppm：1.44 (9H, s), 3.42 (2H, t, J=6.3Hz),

3.58 (2H, q, J=6.3Hz), 4.98 (1H, brs), 7.47 (1H, d, J=8.8Hz),

7.52 (1H, dd, J=8.8Hz, J=1.5Hz), 7.57 chloro- 1, the 2- benzo isoxazole hydrochlorates of (1H, d, J=1.5Hz) (b) 3- (2- aminoethanethios) -5-

According to embodiment 22 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- chloro- 1, the title compound (0.41g, 97%) is made in 2- benzoisoxazoles (0.52g).

Fusing point：201-206 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1588,1524；

H NMR spectroscopy (DMSO-d₆)δppm：3.24 (2H, q, J=7.0Hz), 3.55 (2H, t, J=7.0Hz),

7.75 (1H, dd, J=8.9Hz, J=2.0Hz), 7.83 (1H, d, J=8.9Hz), 7.95 (1H, d, J=2.0Hz),

8.23 (3H, brs)

The fluoro- 4- methyl isophthalic acids of embodiment 393- (2- aminoethanethios) -5-, 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) fluoro- 4- methyl isophthalic acids of -5-, 2- benzoisoxazoles

According to embodiment 17 (b) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- fluoro- 1, the title compound (0.10g, 91%) is made in 2- benzoisoxazoles (0.11g).

H NMR spectroscopy (CDCl₃)δppm：1.44 (9H, s), 2.55 (3H, s), 3.42 (2H, t, J=6.1Hz),

3.58 (2H, td, J=6.1Hz, J=6.1Hz), 5.02 (1H, brs), 7.19-7.34 (2H, m) the fluoro- 4- methyl isophthalic acids of (b) 3- (2- aminoethanethios) -5-, 2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) the fluoro- 4- methyl isophthalic acids of -5-, the title compound (0.07g, quantitative) is made in 2- benzoisoxazoles (0.09g).

Fusing point：209-212 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3103,2963,2901,1499；

H NMR spectroscopy (DMSO-d₆)δppm：2.53 (3H, s), 3.26 (2H, t, J=6.9Hz),

3.55 (2H, t, J=6.9Hz), 7.53-7.65 (2H, m), 8.20 (3H, brs).Fluoro- 4- cyano group -1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 403- (2- aminoethanethios) -5- (fluoro- 4- carbamoyls -1, the 2- benzoisoxazoles of 2- (N- t-butoxycarbonyl aminos) ethylmercapto group -5-

According to embodiment 18 (a) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- fluoro- 1,3- (the fluoro- 4- carboxyls -1 of 2- (N- t-butoxycarbonyl aminos) ethylmercapto group -5- are made in 2- benzoisoxazoles (0.30g), 2- benzoisoxazoles (0.25g, 74%).Then, according to embodiment 18 (b) similar the method reaction and processing, by 3-, (title compound (0.16g, 70%) is made in fluoro- 4- carboxyls -1, the 2- benzoisoxazoles (0.23g) of 2- (N- t-butoxycarbonyl aminos) ethylmercapto group -5-.

H NMR spectroscopy (CDCl₃)δppm：1.43 (9H, s), 3.35 (2H, t, J=6.1Hz),

3.58 (2H, td, J=6.1Hz, J=6.1Hz), 5.03 (1H, brs), 6.02 (1H, brs), 6.29 (1H, brs),

7.37 (1H, t, J=8.9Hz), 7.62 (1H, dd, J=3.8Hz, J=8.9Hz) (b) 3- (fluoro- 4- cyano group -1, the 2- benzoisoxazoles of 2- (N- t-butoxycarbonyl aminos) ethylmercapto group -5-

According to embodiment 19 (a) similar the method reaction and processing; by 3- (the fluoro- 4- carbamoyls -1 of 2- (N- t-butoxycarbonyl aminos) ethylmercapto group -5-; the title compound (0.12g, 92%) is made in 2- benzoisoxazoles (0.14g).

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 3.46 (2H, t, J=6.0Hz),

3.60 (2H, td, J=6.0Hz, J=6.0Hz), 4.97 (1H, brs), 7.45 (1H, t, J=8.9Hz),

7.77 fluoro- 4- cyano group -1, the 2- benzo isoxazole hydrochlorates of (1H, dd, J=3.9Hz, J=8.9Hz) (c) 3- (2- aminoethanethios) -5-

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) the fluoro- 4- cyano group -1 of -5-, the title compound (0.09g, quantitative) is made in 2- benzoisoxazoles (0.11g).

Fusing point：215-219 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3436,3090,3005,1494；

H NMR spectroscopy (DMSO-d₆)δppm：3.27 (2H, t, J=6.9Hz), 3.59 (2H, t, J=6.9Hz),

(1H, dd, J=3.9Hz, the J=9.4Hz) of 7.94 (1H, t, J=9.4Hz), 8.19 (3H, brs), 8.30

Embodiment 413- (2- amino ethoxies) -7- methoxyl group -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methoxyl group -1,2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, the title compound (0.39g, 63%) is made by 3- hydroxyl -7- methoxyl groups -1,2- benzoisoxazoles (0.33g).

Fusing point：98-99℃；

IR composes (KBr) ν_maxcm^-1：3348,1708,1683,1624,1615,1542,1533,

1509；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.64 (2H, q, J=5.1Hz), 4.03 (3H, s),

4.51 (2H, t, J=5.1Hz), 4.97 (1H, brs), 6.95-7.00 (1H, m), 7.15-7.20 (2H, m) (b) 3- (2- amino ethoxies) -7- methoxyl group -1,2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methoxyl groups -1, the title compound (0.23g, 96%) is made in 2- benzoisoxazoles (0.30g).

Fusing point：208-213 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3022,2983,2909,2840,1627,1614,1546,

1509；

H NMR spectroscopy (DMSO-d₆)δppm：3.30 (2H, t, J=5.1Hz), 3.97 (3H, s),

4.61 (2H, t, J=5.1Hz), 7.20-7.25 (1H, m), 7.30-7.35 (2H, m), 8.29 (3H, brs)

The bromo- 3- of embodiment 423- (2- amino ethoxies) -5- methoxycarbonyl group -1,2- benzo isoxazole hydrochlorates (a) 5- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1,2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, by the bromo- 3- hydroxyls -1 of 5-, the title compound (4.80g, 67%) is made in 2- benzoisoxazoles (4.30g) and 2- (N- t-butoxycarbonyl aminos) ethanol.

Fusing point：123-124℃；

IR composes (KBr) ν_maxcm^-1：3313,1699,1683,1611,1545；

H NMR spectroscopy (CDCl₃)δppm：1.46 (3H, s), 3.64 (2H, q, J=5.1Hz),

4.50 (2H, t, J=5.1Hz), 4.92 (1H, brs), 7.33 (1H, d, J=8.9Hz),

7.62 (1H, dd, J=8.9Hz, J=1.9Hz), 7.80 (1H, d, J=1.9Hz) (b) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- methoxycarbonyl group -1,2- benzoisoxazoles

According to embodiment 22 (b) similar the method reaction and processing, by the bromo- 3- of 5- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1, the title compound (0.27g, 29%) is made in 2- benzoisoxazoles (1.00g).

Fusing point：154-155℃；

IR composes (KBr) ν_maxcm^-1：3326,1720,1702,1687,1629,1611,15477；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.66 (2H, q, J=5.1Hz),

3.96 (3H, s), 4.53 (2H, t, J=5.1Hz), 4.97 (1H, brs), 7.47 (1H, d, J=8.8Hz),

8.24 (1H, dd, J=8.8Hz, J=1.6Hz), 8.41 (1H, d, J=1.6Hz).(c) 3- (2- amino ethoxies) -5- methoxycarbonyl group -1,2- benzo isoxazole hydrochlorates

According to embodiment 22 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- methoxycarbonyl groups -1, the title compound (0.16g, 98%) is made in 2- benzoisoxazoles (0.20g).

Fusing point：211-213℃；

IR composes (KBr) ν_maxcm^-1：3300-2400,1718,1625,1610,1544；

H NMR spectroscopy (DMSO-d₆)δppm：3.37 (2H, q, J=5.1Hz), 3.91 (3H, s),

4.63 (2H, t, J=5.1Hz), 7.80 (1H, d, J=8.8Hz), 8.26 (1H, dd, J=8.8Hz, J=1.6Hz),

8.44 (1H, d, J=1.6Hz)

Embodiment 433- (2- amino ethoxies) -5- methylaminos -1,2- benzoisoxazoles dihydrochloride and 3- (2- amino ethoxies) -5- dimethylaminos -1,2- benzoisoxazole dihydrochlorides (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- methylaminos -1,2- benzoisoxazoles and 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- dimethylamino -1,2- benzoisoxazoles

Under 5 DEG C are stirred, to 5- amino -3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1, sodium borohydride (0.66g) is added in tetrahydrofuran (10ml) solution of 2- benzoisoxazoles (0.88g), tetrahydrofuran (10ml) solution of 37% formalin (0.99g) and 3M sulfuric acid (1.0ml) is added dropwise, and stirring 15 minutes is used as in 5 DEG C.After stirring 1.5 hours at room temperature, reactant mixture is cooled to 5 DEG C, 37% formalin (3.0g) and sodium borohydride (0.66g) is added and in stirring 30 minutes at identical temperature.Reactant mixture is poured into frozen water (100ml) and is extracted with ethyl acetate (twice, each 50ml).Organic layer anhydrous magnesium sulfate is dried and filtered.Remove solvent under reduced pressure, residue is through silica gel chromatography, make eluant, eluent with cyclohexane/ethyl acetate (4/1), obtain 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- methylaminos -1,2- benzoisoxazoles (0.49g, 53%) with 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- dimethylaminos -1,2- benzoisoxazole (0.14g, 15%).

The relevant data of 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- methylamino -1,2- benzoisoxazoles.

Fusing point：122-123℃；

IR composes (KBr) ν_maxcm^-1：3392,3317,1695,1673,1636,1611,1548,

1538,1523；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.88 (3H, s), 3.64 (2H, q, J=5.1Hz),

3.79 (1H, brs), 4.49 (2H, t, J=5.1Hz), 4.99 (1H, brs), 6.64 (1H, d, J=2.3Hz),

6.87 (1H, dd, J=8.9Hz, J=2.3Hz), 7.23 (1H, d, J=8.9Hz).

The relevant data of 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- dimethylamino -1,2- benzoisoxazoles.

IR composes (KBr) ν_maxcm^-1：3387,2979,2934,1703,1547,1526,1507；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.97 (6H, s), 3.65 (2H, m),

4.49 (2H, t, J=5.1Hz), 4.99 (1H, brs), 6.78 (1H, d, J=2.4Hz),

7.10 (1H, dd, J=9.2Hz, J=2.4Hz), 7.30 (1H, d, J=9.2Hz) (b) 3- (2- (amino ethoxy) -5- methylamino -1,2- benzoisoxazole dihydrochlorides

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- methylaminos -1, the title compound (0.27g, 99%) is made in 2- benzoisoxazoles (0.30g).

Fusing point：240-250 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3030,2961,2889,2841,2756,2720,2683,

2646,2609,2579,2535,2506,2479,2421,2379,1623,1604,1567,

1544,1528；

H NMR spectroscopy (DMSO-d₆)δppm：2.84 (3H, s), 3.34 (2H, q, J=5.1Hz),

4.61 (2H, t, J=5.1Hz), 7.43 (1H, brs), 7.49 (1H, d, J=8.9Hz), 7.64 (1H, d, J=8.9Hz),

8.34 (3H, brs) (c) 3- (2- (amino ethoxy) -5- dimethylamino -1,2- benzoisoxazole dihydrochlorides

According to embodiment 1 (f) similar the method reaction and processing, the title compound is made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- dimethylamino -1,2- benzoisoxazoles.

Fusing point：150-160 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3500-3200,3100-2800,2700-2400,1626,

1551,1467,1434；

H NMR spectroscopy (DMSO-d₆)δppm：3.06 (6H, s),

3.34 (2H, dd, J=10.6Hz, J=5.5Hz), 4.62 (2H, t, J=5.5Hz), 7.8-7.5 (3H, m),

8.37 (2H, brs)

Embodiment 443- (2- amino ethoxies) -5- difluoro-methoxy -1,2- benzo isoxazole hydrochlorates (a) 5- hydroxyls -3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1,2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, the title compound (0.60g, 62%) is made by 3,5- dihydroxy -1,2- benzoisoxazole (0.50g).

Fusing point：152-153℃；

IR composes (KBr) ν_maxcm^-1：3286,1672,1543,1529；

H NMR spectroscopy (CDCl₃)δppm：1.38 (9H, s), 3.40 (2H, q, J=5.1Hz),

4.34 (2H, t, J=5.1Hz), 6.88 (1H, d, J=2.5Hz), 7.08 (1H, dd, J=8.9Hz, J=2.5Hz),

7.42 (1H, d, J=8.9Hz), 9.68 (1H, s) (b) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- difluoro-methoxy -1,2- benzoisoxazoles

To 5- hydroxyls -3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1, sodium methoxide (90mg) is added in dimethylformamide (4ml) solution of 2- benzoisoxazoles (100mg) and is stirred mixture at room temperature 10 minutes, dichlorodifluoromethane gas is then passed to 20 minutes.Reactant mixture is poured into frozen water (30ml), (twice, each 30ml) is extracted with ethyl acetate, the extract anhydrous magnesium sulfate of merging is dried and filtered.Remove solvent under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (9/1), title compound (19mg, 16%) described in colorless powder is made.

Fusing point：155-156℃；

IR composes (KBr) ν_maxcm^-1：3322,1699,1683,1541；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.51 (2H, t, J=5.1Hz), 4.94 (1H, brs), 6.52 (1H, t, J=73.4Hz), 7.30-7.50 (3H, m) (c) 3- (2- amino ethoxies) -5- difluoro-methoxy -1,2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- difluoro-methoxies -1, the title compound (20mg, 95%) is made in 2- benzoisoxazoles (25mg).

Fusing point：162-164 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1618,1599,1544,1497；

H NMR spectroscopy (DMSO-d₆)δppm：3.34 (2H, q, J=5.1Hz), 4.63 (2H, t, J=5.1Hz),

4.62 (1H, brs), 7.27 (1H, d, J=73.6Hz), 7.54 (1H, dd, J=9.0Hz, J=2.3Hz),

(3H, the brs) of 7.58 (1H, d, J=2.3Hz), 7 75 (1H, d, J=9.0Hz), 8.29

Embodiment 453- (2- amino ethoxies) -7- amino -1,2- benzoisoxazole dihydrochlorides (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- nitro -1,2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, the title compound (2.20g, 68%) is made by 3- hydroxyl -7- nitros -1,2- benzoisoxazoles (1.80g).

Fusing point：116-117℃；

IR composes (KBr) ν_maxcm^-1：3359,3307,1718,1700,1691,1628,1604,

1553,

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.67 (2H, q, J=5.1Hz),

4.57 (2H, t, J=5.1Hz), 4.93 (1H, brs), 7.46 (1H, t, J=8.1Hz), 7.99 (1H, d, J=8.1Hz),

8.41 (1H, d, J=8.1Hz) (b) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- amino -1,2- benzoisoxazoles

According to embodiment 32 (a) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- nitros -1, the title compound (1.26g, 93%) is made in 2- benzoisoxazoles (1.50g).

Fusing point：107-108℃；

IR composes (KBr) ν_maxcm^-1：3438,3349,1700,1640,1604；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.64 (2H, q, J=5.1Hz), 4.03 (2H, s),

4.50 (2H, t, J=5.1Hz), 4.98 (1H, brs), 6.79 (1H, d, J=7.9Hz), 7.00 (1H, d, J=7.9Hz),

7.07 (1H, t, J=7.9Hz) (c) 3- (2- amino ethoxies) -7- amino -1,2- benzoisoxazole dihydrochlorides

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- amino -1, the title compound (0.23g, 98%) is made in 2- benzoisoxazoles (0.26g).

Fusing point：185-195 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,3026,2870,2583,1640,1611,

1582,1553,1525,1509；

H NMR spectroscopy (DMSO-d₆)δppm：3.33 (2H, q, J=5.1Hz), 4.59 (2H, t, J=5.1Hz),

(3H, the brs) of 6.88 (1H, d, J=7.9Hz), 6.97 (1H, d, J=7.9Hz), 7.10 (1H, t, J=7.9Hz), 8.33

Embodiment 463- (2- amino ethoxies) -7- carboxyl -1,2- benzo isoxazole hydrochlorates

According to embodiment 18 (a) similar the method reaction and processing, then react and handle according to the method for embodiment 1 (e), by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1, the title compound (0.036g, 14%) is made in 2- benzoisoxazoles (0.28g).

Fusing point：123-126 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3140,3081,3024,2960,2896,1714,1620,

1615,1553,1548,1495；

H NMR spectroscopy (DMSO-d₆)δppm：3.36 (2H, t, J=5.1Hz), 4.65 (2H, t, J=5.1Hz),

7.53 (1H, t, J=7.1Hz), 8.05 (1H, d, J=7.1Hz), 8.18 (1H, d, J=7.1Hz),

8.32 (3H, brs).

Embodiment 473- (2- amino ethoxies) -5- hydroxyl -1,2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- hydroxyls -1, the title compound (0.16g, 97%) is made in 2- benzoisoxazoles (0.20g).

Fusing point：205-209 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3467,3388,3112,3024,2932,1617,1541,

1528,1503；

H NMR spectroscopy (DMSO-d₆)δppm：3.32 (2H, t, J=5.1Hz), 4.57 (2H, t, J=5.1Hz),

7.01 (1H, d, J=2.5Hz), 7.13 (1H, dd, J=9.0Hz, J=2.5Hz), 7.45 (1H, d, J=9.0Hz),

8.26 (3H, brs), 9.84 (1H, s)

Embodiment 483- (2- amino ethoxies) -5- acetoxyl group -1,2- benzo isoxazole hydrochlorates (a) 5- acetoxy-3s-(2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1,2- benzoisoxazoles

Under 5 DEG C are stirred, to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- hydroxyls -1, triethylamine (44mg) and chloroacetic chloride (34mg) are added in tetrahydrofuran (5ml) solution of 2- benzoisoxazoles (100mg), then by mixture in stirring 15 minutes at identical temperature.Party A's reactant mixture is poured into frozen water (40ml), (twice, each 40ml) is extracted with ethyl acetate, the extract anhydrous magnesium sulfate of merging is dried and filtered.Remove solvent under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (9/1), obtains title compound described in colorless powder (101mg, 88%).

Fusing point：108-110 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3346,1767,1705,1626,1618,1541,1529；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.34 (3H, s), 3.63 (2H, q, J=5.1Hz),

4.50 (2H, t, J=5.1Hz), 4.94 (1H, brs), 7.25 (1H, dd, J=9.0Hz, J=2.2Hz),

7.39 (1H, d, J=2.2Hz), 7.43 (1H, d, J=9.0Hz) (b) 3- (2- amino ethoxies) -5- acetoxyl group -1,2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 5- acetoxy-3s-(2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1, the title compound (59mg, 98%) is made in 2- benzoisoxazoles (80mg).

Fusing point：168-170 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3064,3002,2962,2891,2741,1748,1726,

1618,1592,1545,1510；

H NMR spectroscopy (DMSO-d₆)δppm：2.31 (3H, s), 3.31 (2H, q, J=5.1Hz),

4.62 (2H, t, J=5.1Hz), 7.46 (1H, dd, J=9.0Hz, J=2.2Hz), 7.55 (1H, d, J=2.2Hz),

7.71 (1H, d, J=9.0Hz), 8.27 (3H, brs)

Embodiment 493- (2- amino ethoxies) -7- methylamino -1,2- benzoisoxazole dihydrochlorides (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methylamino -1,2- benzoisoxazoles

According to embodiment 43 (a) similar the method reaction and processing, by 7- amino -3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1, the title compound (0.12g, 13%) is made in 2- benzoisoxazoles (0.88g).

Fusing point：162-164℃；

IR composes (KBr) ν_maxcm^-1：3346,3312,1709,1639,1626,1550,1514；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.99 (3H, d, J=5.0Hz),

3.63 (2H, q, J=5.1Hz), 3.63 (1H, q, J=5.0Hz), 4.49 (2H, t, J=5.1Hz), 4.98 (1H, brs),

6.64 (1H, d, J=7.8Hz), 6.92 (1H, d, J=7.8Hz), 7.15 (1H, t, J=7.8Hz) (b) 3- (2- amino ethoxies) -7- methylamino -1,2- benzoisoxazole dihydrochlorides

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methylaminos -1, the title compound (72mg, 99%) is made in 2- benzoisoxazoles (80mg).

Fusing point：171-181 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3026,2965,2912,2866,2786,2730,2638,

2600,1573,1546,1504；

H NMR spectroscopy (DMSO-d₆)δppm：2.82 (3H, s), 3.33 (2H, q, J=5.1Hz),

(4.59 2H, t, J=5.1Hz), 6.65 (1H, d, J=7.9Hz), 6.89 (1H, d, J=7.9Hz),

7.16 (1H, t, J=7.9Hz), 8.34 (3H, brs)

Embodiment 505- amino -3- (2- amino ethoxies) -1,2- benzoisoxazole dihydrochlorides (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- nitro -1,2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, the title compound (3.60g, 74%) is made by 3- hydroxyl -5- nitros -1,2- benzoisoxazoles (2.70g).

Fusing point：136-137℃；

IR composes (KBr) ν_maxcm^-1：3346,1688,1624,1555,1531；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.67 (2H, q, J=5.1Hz),

4.55 (2H, t, J=5.1Hz), 4.95 (1H, brs), 7.56 (1H, d, J=9.2Hz),

8.46 (1H, dd, J=9.2Hz, J=2.2Hz), 8.62 (1H, d, J=2.2Hz) (b) 5- amino -3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1,2- benzoisoxazoles

According to embodiment 32 (a) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- nitros -1, the title compound (1.65g, 91%) is made in 2- benzoisoxazoles (2.00g).

Fusing point：134-135℃；

IR composes (KBr) ν_maxcm^-1：3470,3442,3384,3360,3325,3276,1699,

1639；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.63 (2H, q, J=5.1Hz), 3.70 (2H, s),

4.47 (2H, t, J=5.1Hz), 4.95 (1H, brs), 6.83 (1H, d, J=2.7Hz),

6.92 (1H, dd, J=8.9Hz, J=2.7Hz), 7.23 (1H, d, J=8.9Hz) (c) 5- amino -3- (2- amino ethoxies) -1,2- benzoisoxazole dihydrochlorides

According to embodiment 1 (f) similar the method reaction and processing, by 5- amino -3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -1, the title compound (0.21g, 99%) is made in 2- benzoisoxazoles (0.24g).

Fusing point：182-202 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3428,3379,2963,2859,2726,2665,2581,

1656,1637,1628,1609,1549,1507；

H NMR spectroscopy (DMSO-d₆)δppm：3.46 (2H, q, J=5.1Hz),

4.63 (2H, t, J=5.1Hz), 7.57 (1H, dd, J=8.9Hz, J=2.0Hz), 7.67 (1H, d, J=2.0Hz),

7.93 (1H, d, J=8.9Hz), 8.35 (3H, brs)

Embodiment 513- (2- amino ethoxies) -4,7- dimethyl -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4,7- dimethyl -1,2- benzoisoxazoles

In under -70 DEG C of blanket of nitrogen and stirring, to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methyl isophthalic acids, butyl lithium (0.7ml is added dropwise in tetrahydrofuran (5ml) solution of 2- benzoisoxazoles (0.15g), 1.6M hexane solutions), by mixture in being stirred 10 minutes at identical temperature, temperature is then risen to 0 DEG C.Reactant mixture is cooled to after -70 DEG C, iodomethane is added and makes temperature rise to 0 DEG C.By reactant mixture please as in frozen water (40ml), (twice, each 40ml) is extracted with ethyl acetate, the extract anhydrous magnesium sulfate of merging is dried and filtered.Remove solvent under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (9/1), obtains title compound described in colorless powder (0.12g, 80%).

Fusing point：78-79℃；

IR composes (KBr) ν_maxcm^-1：3352,1694,1604,1543,1517；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 2.44 (3H, s), 2.56 (3H, s),

4.26 (2H, q, J=5.1Hz), 4.49 (2H, t, J=5.1Hz), 4.90 (1H, brs), 6.89 (1H, d, J=7.3Hz),

7.15 (1H, d, J=7.3Hz) (b) 3- (2- amino ethoxies) -4,7- dimethyl -1,2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4, the title compound (0.08g, quantitative) is made in 7- dimethyl -1,2- benzoisoxazole (0.10g).

Fusing point：222-225 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3300-2400,1601,1561,1542,1511；

H NMR spectroscopy (DMSO-d₆)δppm：2.40 (3H, s), 2.57 (3H, s),

3.35 (2H, t, J=5.1Hz), 4.60 (2H, t, J=5.1Hz), 7.01 (1H, d, J=7.3Hz),

7.31 (1H, d, J=7.3Hz), 8.31 (3H, brs)

The fluoro- 6- methoxyl methyl benzoates of embodiment 523- (2- amino ethoxies) -4- methoxyl group -1,2- benzo isoxazole hydrochlorates (a) 2-

It is stirred at room temperature down, Anhydrous potassium carbonate (6.00g) and iodomethane (6.0ml) is added into 6- fluorosalicylic acids (5.00g) dimethylformamide (50ml) solution, is then stirred vigorously at room temperature 12 hours.After the completion of reaction, reactant mixture is diluted with ether, is washed with water and is dried with anhydrous magnesium sulfate.Remove solvent under reduced pressure, obtain title compound described in oily (5.80g, 98%).

H NMR spectroscopy (CDCl₃)δppm：3.86 (3H, s), 3.93 (3H, s), 6.70-6.80 (2H, m),

7.28-7.37 (1H, m).(b) the fluoro- 6- methoxybenzenes hydroxamic acid of 2-

According to embodiment 1 (b) similar the method reaction and processing, the title compound (44%) is made by the fluoro- 6- methoxyl methyl benzoates of 2- and hydroxylamine hydrochloride.

H NMR spectroscopy (CDCl₃+MeOH-d₄)δppm：3.92 (3H, s), 6.75-6.86 (2H, m),

7.35-7.45 (1H, m).(c) 3- hydroxyls -4- methoxyl group -1,2- benzoisoxazoles

The fluoro- 6- methoxybenzenes hydroxamic acid (2.55g) of 2- and potassium hydroxide (4.50g) are dissolved in butanol (25ml) and flowed back 4 hours.After the completion of reaction, reactant mixture is adjusted to acidity, is extracted with ethyl acetate, extract is washed with water and dried with anhydrous magnesium sulfate.Remove solvent under reduced pressure, residue is recrystallized in isopropyl ether, obtain the title compound (2.05g, 90%).

Fusing point：183-185℃；

H NMR spectroscopy (CDCl₃)δppm：4.02 (3H, s), 6.65 (1H, d, J=8.2Hz),

6.99 (1H, d, J=8.2Hz), 7.50 (1H, t, J=8.2Hz).(d) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- methoxyl group -1,2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, the title compound (81%) is made by 3- hydroxyl -4- methoxyl group -1,2- benzoisoxazoles.

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.65 (2H, s), 3.96 (3H, s),

4.50 (2H, t, J=5.1Hz), 5.06 (1H, brs), 6.61 (1H, d, J=8.2Hz), 7.02 (1H, d, J=g.2Hz),

7.43 (1H, t, J=g.2Hz) (e) 3- (2- amino ethoxies) -4- methoxyl group -1,2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, the title compound (82%) is made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- methoxyl group -1,2- benzoisoxazoles.

Fusing point：193-197℃；

IR composes (KBr) ν_maxcm^-1：3435,3220,2960,1630,1615,1535,1505；

H NMR spectroscopy (DMSO-d₆)δppm：3.34 (2H, t, J=5.2Hz), 3.92 (3H, s),

4.60 (2H, t, J=5.2Hz), 6.86 (1H, d, J=8.4Hz), 7.17 (1H, d, J=8.4Hz),

7.58 (1H, t, J=8.4Hz)

Embodiment 533- (2- amino ethoxies) -4- methoxyl group -7- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, the title compound is made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- methoxyl group -1,2- benzoisoxazoles.

Fusing point：208-211℃；

IR composes (KBr) ν_maxcm^-1：3160,2840,1640,1620,1540,1520,1510；

H NMR spectroscopy (DMSO-d₆)δppm：2.35 (3H, s), 3.33 (2H, t, J=5.4Hz),

3.89 (3H, s), 4.59 (2H, t, J=5.4Hz), 6.75 (1H, d, J=8.1Hz), 7.37 (1H, d, J=8.1Hz),

8.30 (3H, brs)

Fluoro- 1, the 2- benzo isoxazole hydrochlorates (a) 2 of embodiment 543- (2- amino ethoxies) -4-, 6- difluoro benzohydroxamic acids

According to embodiment 1 (b) similar the method reaction and processing, the title compound (65%) is made by 2,6- difluoro-benzoic acids methyl esters and hydroxylamine hydrochloride.

H NMR spectroscopy (DMSO-d₆)δppm：7.14-7.25 (2H, m), 7.50-7.60 (1H, m),

9.40 (1H, brs), 11.15 (1H, brs).(b) fluoro- 1, the 2- benzoisoxazoles of 3- hydroxyls -4-

According to embodiment 52 (c) similar the method reaction and processing, the title compound (36%) is made by 2,6- difluoro benzohydroxamic acids.

Fusing point：175-178℃；

H NMR spectroscopy (DMSO-d₆)δppm：7.09 (1H, t, J=8.5Hz), 7.40 (1H, d, J=8.5Hz),

7.57-7.65 (1H, m).(c) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) fluoro- 1, the 2- benzoisoxazoles of -4-

According to embodiment 1 (e) similar the method reaction and processing, the title compound (67%) is made by fluoro- 1, the 2- benzoisoxazoles of 3- hydroxyls -4-.

H NMR spectroscopy (CDCl₃)δppm：1.47 (9H, s), 3.65 (2H, m), 4.51 (2H, t, J=5.1Hz),

4.90-5.06 (1H, brs), 6.91 (1H, t, J=8.5Hz), 7.23 (1H, t, J=8.5Hz), 7.44-7.52 (1H, m) fluoro- 1, the 2- benzo isoxazole hydrochlorates of (d) 3- (2- amino ethoxies) -4-

According to embodiment 1 (f) similar the method reaction and processing, the title compound (75%) is made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) fluoro- 1,2- benzoisoxazoles of -4-.

Fusing point：230-233 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3435,2970,1635,1620,1545,1520,1510；

H NMR spectroscopy (DMSO-d₆)δppm：3.34 (2H, t, J=5.2Hz), 4.66 (2H, t, J=5.2Hz),

7.21 (1H, t, J=8.3Hz), 7.53 (1H, d, J=8.3Hz), 7.68-7.74 (1H, m), 8.35 (3H, brs)

The fluoro- 5- methyl isophthalic acids of embodiment 553- (2- amino ethoxies) -4-, 2- benzo isoxazole hydrochlorates and the fluoro- 7- methyl isophthalic acids of 3- (2- amino ethoxies) -4-, 2- benzo isoxazole hydrochlorates

According to embodiment 51 (a), then react and handle according to embodiment 1 (f) the similar method, by 3- (2- amino ethoxies) -4- fluoro- 1, the fluoro- 5- methyl isophthalic acids of 3- (2- amino ethoxies) -4- are made in 2- benzoisoxazoles, 2- benzo isoxazole hydrochlorates and the fluoro- 7- methyl isophthalic acids of 3- (2- amino ethoxies) -4-, 2- benzo isoxazole hydrochlorates.(a) the fluoro- 5- methyl isophthalic acids of 3- (2- amino ethoxies) -4-, the relevant data of 2- benzo isoxazole hydrochlorates.

Fusing point：201-208℃；

IR composes (KBr) ν_maxcm^-1：3430,3305,2840,1645,1615,1540,1515；

H NMR spectroscopy (DMSO-d₆)δppm：2.32 (3H, s), 3.34 (2H, q, J=5.0Hz),

4.64 (2H, t, J=5.0Hz), 7.42 (2H, d, J=8.4Hz), 7.60 (1H, t, J=8.4Hz), the 8.27 fluoro- 7- methyl isophthalic acids of (3H, brs) (b) 3- (2- amino ethoxies) -4-, the relevant data of 2- benzo isoxazole hydrochlorates.

Fusing point：196-202℃；

IR composes (KBr) ν_maxcm^-1：2975,1635,1550,1520；

H NMR spectroscopy (DMSO-d₆)δppm：2.42 (3H, s), 3.35 (2H, t, J=5.2Hz),

4.65 (2H, t, J=5.2Hz), 7.10 (1H, t, J=8.9Hz), 7.47-7.51 (1H, m), 8.32 (3H, brs)

The chloro- 7- methyl isophthalic acids of embodiment 563- (2- aminoethanethios) -5-, 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) chloro- 7- methyl isophthalic acids of -5-, 2- benzoisoxazoles

According to embodiment 17 (b) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- chloro- 1, the title compound (0.13g, 62%) is made in 2- benzoisoxazoles (0.20g).

H NMR spectroscopy (CDCl₃)δppm：1.44 (9H, s), 2.51 (3H, s), 3.40 (2H, t, J=6.3Hz),

3.58 (2H, q, J=6.3Hz), 5.07 (1H, brs), 7.29 (1H., s), 7.36 (1H, s).(b) the chloro- 7- methyl isophthalic acids of 3- (2- aminoethanethios) -5-, 2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) the chloro- 7- methyl isophthalic acids of -5-, the title compound (0.10g, quantitative) is made in 2- benzoisoxazoles (0.12g).

Fusing point：205-208 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：2966,2927,2848,2802,1481；

H NMR spectroscopy (DMSO-d₆)δppm：2.50 (3H, s), 3.23 (2H, t, J=6.9Hz),

3.53 (2H, t, J=6.9Hz), 7.62 (1H, s), 7.74 (1H, s), 8.19 (3H, brs)

Chloro- 7- cyano group -1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 573- (2- aminoethanethios) -5- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) chloro- 7- carboxyls -1,2- benzoisoxazoles of -5-

According to embodiment 18 (a) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- chloro- 1, the title compound (0.42g, 72%) is made in 2- benzoisoxazoles (0.51g).(b) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) chloro- 7- carbamoyls -1, the 2- benzoisoxazoles of -5-

According to embodiment 18 (b) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) the chloro- 7- carboxyls -1 of -5-, the title compound (0.17g, 85%) is made in 2- benzoisoxazoles (0.20g).

IR composes (KBr) ν_maxcm^-1：3471,3354,3143,1693,1678；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 3.45 (2H, t, J=6.1Hz),

3.59 (2H, q, J=6.1Hz), 4.96 (1H, brs), 5.97 (1H, brs), 7.12 (1H, brs), 7.73 (1H, s),

8.34 (1H, s) (c) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) chloro- 7- cyano group -1, the 2- benzoisoxazoles of -5-

According to embodiment 19 (a) similar the method reaction and processing; by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) the chloro- 7- carbamoyls -1 of -5-; the title compound (0.13g, 90%) is made in 2- benzoisoxazoles (0.15g).

IR composes (KBr) ν_maxcm^-1：3366,2240,1685；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 3.46 (2H, t, J=6.2Hz),

3.60 (2H, q, J=6.2Hz), 4.96 (1H, brs), 7.81 (1H, s), 7.84 (1H, s) chloro- 7- cyano group -1, the 2- benzo isoxazole hydrochlorates of (d) 3- (2- aminoethanethios) -5-

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) the chloro- 7- cyano group -1 of -5-, the title compound (0.10g, quantitative) is made in 2- benzoisoxazoles (0.12g).

Fusing point：178-181 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3432,3038,2990,2235,1607,1598,1588；

H NMR spectroscopy (DMSO-d₆)δppm：3.25 (2H, t, J=7.0Hz), 3.57 (2H, t, J=7.0Hz),

8.23 (3H, brs), 8.42 (1H, s), 8.49 (1H, s).

Embodiment 583- (2- amino ethoxies) -5- chloropyridines simultaneously [3,2-d] isoxazole hydrochlorates (a) 2,5- dichloro-nicotinic acid methyl esters

In under ice cooling stirring, it is dissolved in methanol (30ml), then stirs 30 minutes at room temperature to the chloronicotinoyl chlorides of 2,5- bis- (5.0g).Remove solvent under reduced pressure, residue is dissolved in ether and with saturated sodium bicarbonate aqueous solution and salt water washing.Extract anhydrous magnesium sulfate is dried and filtered.Remove solvent under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (30/1), obtains the title compound (4.2g, 86%).

H NMR spectroscopy (CDCl₃)δppm：3.98 (3H, s), 8.16 (1H, s), 8.48 (1H, s).(b) 2,5- dichloropyridines -3- carboxylics oxime acid

According to embodiment 10 (b) similar the method reaction and processing, the title compound (3.3g, 79%) is made by 2,5- dichloro-nicotinic acids methyl esters (4.2g).

IR composes (KBr) ν_maxcm^-1：3187,3073,3058,2985,2906,2851,1661,

1575,1553；

H NMR spectroscopy (DMSO-d₆)δppm：8.11 (1H, s), 8.58 (1H, s), 9.50 (1H, s),

11.40 (1H, s).(c) 3- hydroxyls -5- chloropyridines simultaneously [3,2-d] isoxazoles

According to embodiment 10 (c) similar the method reaction and processing, the title compound (0.82g, 66%) is made by 2,5- dichloropyridine -3- carboxylics oxime sour (1.5g).

IR composes (KBr) ν_maxcm^-1：3193,3166,3069,3055,3003,2919,2821,2783,2734,

2689,2633,2587,2550,1697,1615,1602,1554,1508；

H NMR spectroscopy (DMSO-d₆)δppm：8.40 (1H, s), 8.63 (1H, s), 12.90 (1H, brs).(d) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- chloropyridines simultaneously [3,2-d] isoxazoles

According to embodiment 1 (e) similar the method reaction and processing, by 3- hydroxyl -5- chloropyridines, simultaneously [title compound (0.27g, 73%) is made in 3,2-d] isoxazoles.

IR composes (KBr) ν_maxcm^-1：3360,1709,1701,1599,1537,1525；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.64 (2H, q, J=5.2Hz),

4.52 (2H, t, J=5.2Hz), 4.90 (1H, brs), 8.03 (1H, s), 8.54 (1H, s).(e) 3- (2- amino ethoxies) -5- chloropyridines simultaneously [3,2-d] isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- chloropyridines simultaneously [3, the title compound (0.19g, quantitative) is made in 2-d] isoxazoles (0.21g).

Fusing point：225-230 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3065,3036,2978,2900,1604,1598,1535；

H NMR spectroscopy (DMSO-d₆)δppm：3.34 (2H, t, J=5.0Hz), 4.64 (2H, t, J=5.0Hz),

8.25 (3H, brs), 8.50 (1H, s), 8.76 (1H, s).

Embodiment 593- (2- aminoethanethios) -5- chloropyridines simultaneously [3,2-d] isoxazole hydrochlorates (a) 3,5- dichloropyridines simultaneously [3,2-d] isoxazoles

According to method reaction similar described in embodiment 16 and processing, by 5- chloro-3-hydroxyls pyrrole, simultaneously [title compound (0.21g, 73%) is made in 3,2-d] isoxazoles (0.27g).

H NMR spectroscopy (CDCl₃)δppm：8.08 (1H, s), 8.64 (1H, s).(b) 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- chloropyridines simultaneously [3,2-d] isoxazoles

According to embodiment 26 (b) similar the method reaction and processing, by 3,5- dichloropyridines, simultaneously [title compound (0.12g, 71%) is made in 3,2-d] isoxazoles (0.10g).

IR composes (KBr) ν_maxcm^-1：3369,1688,1530；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.44 (2H, t, J=6.3Hz),

3.59 (2H, q, J=6.3Hz), 4.97 (1H, brs), 7.95 (1H, s), 8.57 (1H, s).(c) 3- (2- aminoethanethios) -5- chloropyridines simultaneously [3,2-d] isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethylmercapto group) -5- chloropyridines simultaneously [3, the title compound (0.08g, quantitative) is made in 2-d] isoxazoles (0.10g).

Fusing point：194-198 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3040,3001,2909,1586,1515；

H NMR spectroscopy (DMSO-d₆)δppm：3.24 (2H, t, J=7.1Hz), 3.55 (2H, t, J=7.1Hz),

8.17 (3H, brs), 8.69 (1H, s), 8.79 (1H, s).

Embodiment 603- (2- amino ethoxies) -4- methoxycarbonyl group -7- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- methoxycarbonyl group -7- methyl isophthalic acids, 2- benzoisoxazoles

According to embodiment 22 (b) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methyl isophthalic acids, the title compound (91%) is made in 2- benzoisoxazoles.

Fusing point：62-64℃；

IR composes (KBr) ν_maxcm^-1：3380,1715,1703,1621,1591,1534,1513；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.56 (3H, s), 3.66 (2H, q),

3.97 (3H, s), 4.51 (2H, t, J=5.1Hz), 5.33 (1H, brs), 7.35 (1H, d, J=7.6Hz),

7.78 (1H, d, J=7.6Hz) (b) 3- (2- amino ethoxies) -4- methoxycarbonyl group -7- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- methoxycarbonyl group -7- methyl isophthalic acids, the title compound (97%) is made in 2- benzoisoxazoles.

Fusing point：200-202 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3184,3003,2953,1699,1608,1591,1534,

1511；

H NMR spectroscopy (DMSO-d₆)δppm：2.53 (3H, s), 3.34 (2H, t, J=5.1Hz),

3.91 (3H, s), 4.61 (2H, t, J=5.1Hz), 7.59 (1H, d, J=7.5Hz), 7.76 (1H, d, J=7.5Hz),

8.19 (3H, brs)

Embodiment 613- (2- amino ethoxies) -4- carbamoyl -7- methyl isophthalic acids; 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carbamoyl -7- methyl isophthalic acids, 2- benzoisoxazoles

According to embodiment 23 (a) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methyl isophthalic acids, the title compound (83%) is made in 2- benzoisoxazoles.

Fusing point：140-141℃；

IR composes (KBr) ν_maxcm^-1：3451,3351,3199,1705,1675,1618,1585,

1539,1525,1509；

H NMR spectroscopy (CDCl₃)δppm：1.43 (9H, s), 2.56 (3H, s),

3.70 (2H, q, J=5.1Hz), 4.61 (2H, t ,=5.1Hz), 4.94 (1H, brs), 5.89 (1H, brs),

7.41 (1H, d, J=7.6Hz), 7.80 (1H, brs), 8.06 (1H, d, J=7.6Hz) (b) 3- (2- amino ethoxies) -4- carbamoyl -7- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing; by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carbamoyl -7- methyl isophthalic acids, the title compound (99%) is made in 2- benzoisoxazoles.

Fusing point：202-205 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3435,3347,3293,3203,2950,1901,1687,

1659,1608,1581,1544,1512；

H NMR spectroscopy (DMSO-d₆)δppm：2.50 (3H, s), 3.34 (2H, t, J=5.1Hz),

(4.64 2H, t, J=5.1Hz), 7.53 (2H, s), 7.64 (1H, brs), 7.92 (1H, brs), 8.22 (3H, brs)

Embodiment 623- (2- amino ethoxies) -4- cyano group -7- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- cyano group -7- methyl isophthalic acids, 2- benzoisoxazoles

According to embodiment 24 (a) similar the method reaction and processing; by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- carbamoyl -7- methyl isophthalic acids, the title compound (95%) is made in 2- benzoisoxazoles.

Fusing point：84-85℃；

IR composes (KBr) ν_maxcm^-1：3452,3397,2231,1716,1597,1552,1541,

1509；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 2.59 (3H, s),

3.68 (2H, q, J=5.1Hz), 4.54 (2H, t, J=5.1Hz), 5.10 (1H, brs), 7.40 (1H, d, J=7.4Hz),

7.54 (1H, d, J=7.4Hz) (b) 3- (2- amino ethoxies) -4- cyano group -7- methyl isophthalic acids, 2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- cyano group -7- methyl isophthalic acids, the title compound (96%) is made in 2- benzoisoxazoles.

Fusing point：208-211℃；

IR composes (KBr) ν_maxcm^-1：3099,3036,2966,2908,2873,2850,2754,

2733,2232,1598,1542,1514；

H NMR spectroscopy (DMSO-d₆)δppm：2.56 (3H, s), 3.39 (2H, t, J=5.1Hz),

(3H, the brs) of 4.71 (2H, t, J=5.1Hz), 7.68 (1H, d, J=7.5Hz), 7.87 (1H, d, J=7.5Hz), 8.26

Embodiment 633- (2- amino ethoxies) -7- methyl -4- methyl mercaptos -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methyl -4- methyl mercapto -1,2- benzoisoxazoles

Under -70 DEG C of blanket of nitrogen and stirring, to 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methyl isophthalic acids, butyl lithium (0.75ml is added dropwise in tetrahydrofuran (20ml) solution of 2- benzoisoxazoles (0.15g), 1.6M hexane solutions), by mixture in being stirred 15 minutes at identical temperature, dimethyl disulphide (0.11g) is subsequently added.Reactant mixture is poured into frozen water (40ml), (twice, each 40ml) is extracted with ethyl acetate, the extract anhydrous magnesium sulfate of merging is dried and filtered.Remove solvent under reduced pressure, residue makees eluant, eluent through silica gel chromatography with cyclohexane/ethyl acetate (9/1), obtains title compound described in colorless powder (0.15g, 88%).

Fusing point：85-86℃；

IR composes (KBr) ν_maxcm^-1：3376,1699,1627,1589,1549,1533；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.44 (3H, s), 2.53 (3H, s),

3.66 (2H, q, J=5.1Hz), 4.49 (2H, t, J=5.1Hz), 5.07 (1H, brs), 6.86 (1H, d, J=7.5Hz),

7.22 (1H, d, J=7.5Hz) (b) 3- (2- amino ethoxies) -7- methyl -4- methyl mercapto -1,2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, the title compound (94%) is made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- methyl -4- methyl mercapto -1,2- benzoisoxazoles.

Fusing point：216-218 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：2940,2917,2883,1629,1593,1541,1508；

H NMR spectroscopy (DMSO-d₆)δppm：2.39 (3H, s), 2.53 (2H, s),

3.34 (2H, t, J=5.1Hz), 4.61 (2H, t, J=5.1Hz), 7.03 (1H, d, J=7.5Hz),

7.41 (1H, d, J=7.5Hz), 8.26 (3H, brs)

The chloro- 4- methyl isophthalic acids of embodiment 643- (2- amino ethoxies) -7-, 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 4- methyl isophthalic acids of -7-, 2- benzoisoxazoles

According to embodiment 51 (a) similar the method reaction and processing, the title compound, yield 93% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -7-.

IR composes (KBr) ν_maxcm^-1：3355,1691,1605,1551,1536；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 2.57 (3H, s),

3.65 (2H, q, J=5.1Hz), 4.50 (2H, t ,=5.1Hz), 4.87 (1H, brs), 6.94 (1H, d, J=7.8Hz),

The 7.37 chloro- 4- methyl isophthalic acids of (1H, d, J=7.8Hz) (b) 3- (2- amino ethoxies) -7-, 2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) the chloro- 4- methyl isophthalic acids of -7-, the title compound, yield 98% is made in 2- benzoisoxazoles.

Fusing point：215-218 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3194,2967,2892,1606,1540；

H NMR spectroscopy (DMSO-d₆)δppm：2.60 (3H, s), 3.35 (2H, t, J=5.1Hz),

(3H, the brs) of 4.63 (2H, t, J=5.1Hz), 7.17 (1H, d, J=7.7Hz), 7.66 (1H, d, J=7.7Hz), 8.24

Embodiment 653- (2- amino ethoxies) -5, the chloro- 4- methyl isophthalic acids of 7- bis-, 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 4- methyl isophthalic acids of -5,7- bis-, 2- benzoisoxazoles

According to embodiment 51 (a) similar the method reaction and processing, the title compound, yield 95% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -5,7- bis-.

Fusing point：109-111℃；

IR composes (KBr) ν_maxcm^-1：3354,1697,1616,1552,1528；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.59 (3H, s),

3.63 (2H, q, J=5.1Hz), 4.50 (2H, t, J=5.1Hz), 4.93 (1H, brs), 7.58 (1H, s) the chloro- 4- methyl isophthalic acids of (b) 3- (2- amino ethoxies) -5,7- bis-, 2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) the chloro- 4- methyl isophthalic acids of -5,7- bis-, the title compound, yield 99% is made in 2- benzoisoxazoles.

Fusing point：222-225 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3062,2970,2897,2770,1618,1596,1542,

1521；

H NMR spectroscopy (DMSO-d₆)δppm：2.56 (3H, s), 3.38 (2H, t, J=5.1Hz),

4.62 (2H, t, J=5.1Hz), 7.90 (1H, s), 8.28 (3H, brs).

Embodiment 663- (2- amino ethoxies) -7- carbamoyls -5- chloro- 1; 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -7- carbamoyls -5-

According to embodiment 18 (a), then react and handle according to embodiment 18 (b) the similar method, the title compound, yield 88% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -5-.

IR composes (KBr) ν_maxcm^-1：3428,3375,3297,3187,1691,1658,1620,

1560,1531；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.66 (2H, q, J=5.1Hz),

4 53 (2H, t, J=5.1Hz), 4.94 (1H, brs), 5.99 (1H, brs), 7.08 (1H, brs),

7.80 (1H, d, J=2.1Hz), 8.31 chloro- 1, the 2- benzo isoxazole hydrochlorates of (1H, d, J=2.1Hz) (b) 3- (2- amino ethoxies) -7- carbamoyls -5-

According to embodiment 17 (c) similar the method reaction and processing, the title compound, yield 98% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -7- carbamoyls -5-.

Fusing point：232-237 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3450,3339,3290,3238,3164,3082,3047,3011,

2952,2878,2847,2818,2766,2688,1672,1626,1608,1594,1547,

1520；

H NMR spectroscopy (DMSO-d₆)δppm：3.47 (2H, t, J=5.1Hz), 4.63 (2H, t, J=5.1Hz),

7.94 (1H, brs), 7.97 (1H, brs), 8.03 (1H, d, J=2.2Hz), 8.05 (1H, d, J=2.2Hz),

(8.33 3H, brs)

Chloro- 7- cyano group -1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 673- (2- amino ethoxies) -5- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 7- cyano group -1,2- benzoisoxazoles of -5-

According to embodiment 24 (a) similar the method reaction and processing, the title compound, yield 92% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 7- carbamoyls -1,2- benzoisoxazoles of -5-.

Fusing point：141-143℃；

IR composes (KBr) ν_maxcm^-1：3364,2244,1684,1609,1547,1527；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 3.62 (2H, q, J=5.1Hz),

4.53 (2H, t, J=5.1Hz), 4.90 (1H, brs), 7.81 (1H, d, J=2.2Hz), 7.88 chloro- 7- cyano group -1, the 2- benzo isoxazole hydrochlorates of (1H, d, J=2.2Hz) (b) 3- (2- amino ethoxies) -5-

According to embodiment 17 (c) similar the method reaction and processing, the title compound, yield 94% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 7- cyano group -1,2- benzoisoxazoles of -5-.

Fusing point：211-214 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3070,3047,2943,2878,2810,2769,2739,2685,

2637,2243,1611,1586,1548,1507；

8.32 (1H, d, J=2.2Hz), 8.39 (3H, brs), 8.48 (1H, d, J=2.2Hz).

Embodiment 683- (2- amino ethoxies) pyrido [2,3-d] isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) pyrido [2,3-d] isoxazoles

According to embodiment 1 (e) similar the method reaction and processing, by 3- pyridones, simultaneously [title compound, yield 63% is made in 2,3-d] isoxazoles.

Fusing point：94-95℃；

IR composes (KBr) ν_maxcm^-1：3374,3247,1754,1698,1678,1587,1529；

H NMR spectroscopy (CDCl₃)δppm：1.44 (9H, s), 3.68 (2H, q, J=5.1Hz),

4.59 (2H, t, J=5.1Hz), 5.12 (1H, brs), 7.50 (1H, dd, J=8.6Hz, J=4.4Hz),

7.81 (1H, dd, J=g 6Hz, J=1.4Hz), 8.68 (1H, dd, J=4 4Hz, J=1.4Hz) (b) 3- (2- amino ethoxies) pyrido [2,3-d] isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl), [title compound, yield 89% is made in 2,3-d] isoxazoles to pyrido.

Fusing point：217-222 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3070,3020,2980,2911,2870,2783,2700,2658,

2601,1631,1586,1541；

H NMR spectroscopy (DMSO-d₆)δppm：3.35 (2H, t, J=5.1Hz),

4.72 (2H, t, J=5.1Hz), 7.73 (1H, dd, J=8.6Hz, J=4.4Hz), 8.21 (1H, d, J=8.6Hz),

8.32 (3H, brs), 8.73 (1H, d, J=4.4Hz)

Embodiment 693- (2- amino ethoxies) -4- trifluoromethyl pyridines simultaneously [3,2-d] isoxazole hydrochlorates (a) 4- trifluoromethyl nicotinic acid N- oxides

4- trifluoromethyl nicotinic acids (5.00g) are dissolved in acetic acid (20ml) and 31% hydrogen peroxide (5ml) solution and in stirring 10 hours at 100 DEG C.Remove solvent under reduced pressure, obtain title compound described in solid-like (5.40g, quantitative).

Fusing point：210-215 DEG C (decomposition)；

H NMR spectroscopy (CDCl₃)δppm：7.61 (1H, d, J=6.9Hz), 8.32 (1H, d, J=6.9Hz),

8.56 (1H, s).(b) the chloro- 4- trifluoromethyl nicotinic acids methyl esters of 2-

Phosphoryl chloride phosphorus oxychloride (4.0ml) and phosphorus pentachloride (4.0g) are added in 4- trifluoromethyl nicotinic acid N- oxides (2.00g) and by mixture in stirring 4 hours at 100 DEG C.Remove phosphoryl chloride phosphorus oxychloride under reduced pressure.Under ice-cooling, methanol (30ml) is added into residue, is then stirred 30 minutes at room temperature.Added into reactant mixture after sodium bicarbonate aqueous solution, pH is adjusted to alkalescence, mixture ether is extracted and is washed with water, extract is dried with anhydrous magnesium sulfate.After filtering, solvent is removed under reduced pressure, then residue makees eluant, eluent through silica gel chromatography with hexane/ethyl acetate (9/1), obtain title compound described in oily (310mg, 14%).

H NMR spectroscopy (CDCl₃)δppm：4.01 (3H, s), 7.54 (1H, d, J=5.3Hz),

8.65 (1H, d, J=5.3Hz).(c) 3- hydroxyls -4- trifluoromethyl pyridines simultaneously [3,2-d] isoxazoles

At room temperature, the aqueous solution (5ml) of hydroxylamine hydrochloride (450mg) and sodium hydroxide (520mg) is added in the chloro- 4- trifluoromethyl nicotinic acids methyl esters (300mg) of 2-, then stirred mixture at room temperature 5 days.After the aqueous hydrochloric acid solution that dilution is added into reactant mixture, pH is adjusted to acidity, and mixture is extracted with ethyl acetate.The extract of merging is dried with anhydrous magnesium sulfate.Remove solvent under reduced pressure, residue is recrystallized in ethyl acetate, obtain title compound described in solid-like (180mg, 67%).

Fusing point：196-202℃；

H NMR spectroscopy (DMSO-d₆)δppm：7.81 (1H, d, J=4.9Hz), 8.88 (1H, d, J=4.9Hz),

13.30 (1H, brs).(d) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- trifluoromethyl pyridines simultaneously [3,2-d] isoxazoles

According to embodiment 1 (e) similar the method reaction and processing, by 3- hydroxyl -4- trifluoromethyl pyridines, simultaneously [title compound, yield 75% is made in 3,2-d] isoxazoles and 2- (N- t-butoxycarbonyl aminos) ethanol.

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 3.65 (2H, q, J=5.2Hz),

4.55 (2H, t, J=5.2Hz), 4.90 (1H, brs), 7.56 (1H, d, J=4.9Hz), 8.77 (1H, d, J=4.9Hz) (e) 3- (2- amino ethoxies) -4- trifluoromethyl pyridines simultaneously [3,2-d] isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl), simultaneously [title compound, yield 96% is made in 3,2-d] isoxazoles to -4- trifluoromethyl pyridines.

Fusing point：203-207℃；

IR composes (KBr) ν_maxcm^-1：3100,2970,1600,1540；

H NMR spectroscopy (DMSO-d₆)δppm：3.34 (2H, t, J=5.5Hz),

(1H, d, the J=4.8Hz) of 4.71 (2H, t, J=5.5Hz), 7.94 (1H, d, J=4.8Hz), 8.26 (3H, brs), 8.97

Embodiment 703- (2- amino ethoxies) -7- Trifluoromethyl-1s, the fluoro- 3- trifluoromethyl benzoic acid methyl esters of 2- benzo isoxazole hydrochlorates (a) 2-

According to embodiment 52 (a) similar the method reaction and processing, the title compound as described in being made oily in the fluoro- 3- trifluoromethylbenzoic acids of 2-.

H NMR spectroscopy (CDCl₃)δppm：3.96 (3H, s), 7.31 (1H, t, J=5.0Hz),

7.79 (1H, t, J=5.0Hz), 8.18 (1H, t, J=5.0Hz).(b) the fluoro- 3- trifluoromethyls benzohydroxamic acids of 2-

According to embodiment 52 (b) similar the method reaction and processing, the title compound is made by the fluoro- 3- trifluoromethyl benzoic acid methyl esters of 2-.

H NMR spectroscopy (DMSO-d₆)δppm：7.46 (1H, t, J=5.0Hz), 7.82 (2H).(c) 3- hydroxyls -7- Trifluoromethyl-1s, 2- benzoisoxazoles

According to embodiment 52 (c) similar the method reaction and processing, the title compound as described in being made solid-like in the fluoro- 3- trifluoromethyls benzohydroxamic acids of 2-.

Fusing point：204-207℃；

H NMR spectroscopy (DMSO-d₆)δppm：7.54 (1H, t, J=7.6Hz), 7.98 (1H, d, J=7.6Hz),

8.09 (1H, d, J=7.7Hz), 12.80 (1H, brs).(d) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- Trifluoromethyl-1s, 2- benzoisoxazoles

According to embodiment 1 (e) similar the method reaction and processing, by 3- hydroxyl -7- Trifluoromethyl-1s, title compound, yield 65% described in solid-like is made in 2- benzoisoxazoles and 2- (N- t-butoxycarbonyl aminos) ethanol.

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 3.65 (2H, q, J=5.2Hz),

4.54 (2H, t, J=5.2Hz), 4.52 (1H, brs), 7.39 (1H, t, J=7.6Hz), 7.79 (1H, d, J=7 6Hz),

7.85 (1H, d, J=7.6Hz) (e) 3- (2- amino ethoxies) -7- Trifluoromethyl-1s, 2- benzo isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -7- Trifluoromethyl-1s, the title compound, yield 77% is made in 2- benzoisoxazoles.

Fusing point：190-194℃；

IR composes (KBr) ν_maxcm^-1：2970,2905,1615,1555,1510；

H NMR spectroscopy (DMSO-d₆)δppm：3.37 (2H, t, J=5.1Hz),

4.68 (2H, t, J=5.1Hz), 7.62 (1H, t, J=7.6Hz), 8.09 (1H, d, J=7.6Hz),

8.16 (1H, d, J=7.6Hz), 8.44 (3H, brs)

Chloro- 1,2- benzo isoxazole hydrochlorates (a) 3- of embodiment 713- (2- amino ethoxies) -4- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -4-

According to embodiment 1 (e) similar the method reaction and processing, the title compound, yield 63% are made by chloro- 1, the 2- benzoisoxazoles of 3- hydroxyls -4- and 2- (N- t-butoxycarbonyl aminos) ethanol.

Fusing point：110-111℃；

IR composes (KBr) ν_maxcm^-1：3357,1691,1607,1537；

H NMR spectroscopy (DMSO-d₆)δppm：1.46 (9H, s), 3.66 (2H, q, J=5.1Hz),

4.51 (2H, t, J=5.1Hz), 4.99 (1H, brs), 7.23 (1H, d, J=7.6Hz), 7.34 (1H, d, J=8.4Hz),

7 44 chloro- 1, the 2- benzo isoxazole hydrochlorates of (1H, dd, J=8.4Hz, J=7.6Hz) (b) 3- (2- amino ethoxies) -4-

According to embodiment 17 (c) similar the method reaction and processing, the title compound, yield 99% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 1,2- benzoisoxazoles of -4-.

Fusing point：221-226 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3440,3070,3006,2969,2898,1610,1538,

1515；

H NMR spectroscopy (DMSO-d₆)δppm：3.35 (2H, t, J=5.1Hz), 4.65 (2H, t, J=5.4Hz),

7.42-7.49 (1H, m), 7.62-7.7 1 (2H, m), 8.23 (3H, brs).

Embodiment 723- (2- amino ethoxies) -6- picolines simultaneously [chloro- 6- methylnicotinic acids ethyl esters of 3,2-d] isoxazole hydrochlorates (a) 2-

According to embodiment 1 (a) similar the method reaction and processing, the title compound is made by the chloro- 6- methylnicotinic acids of 2-.

H NMR spectroscopy (CDCl₃)δppm：1.41 (3H, t, J=7.2Hz), 2.59 (3H, s),

4.41 (2H, q, J=7.2Hz), 7.16 (1H, d, J=7.2Hz), 8.08 (1H, d, J=7.2HZ).(b) the chloro- 6- picolines -3- carboxylics oxime acid of 2-

According to embodiment 10 (b) similar the method reaction and processing, the title compound is made by the chloro- 6- methylnicotinic acids ethyl esters of 2-.

H NMR spectroscopy (DMSO-d₆)δppm：2.51 (3H, s), 7.33 (1H, d, J=7.8Hz),

7.75 (1H, d, J=7.8Hz).(c) 3- hydroxyls -6- picolines simultaneously [3,2-d] isoxazoles

According to embodiment 10 (c) similar the method reaction and processing, the title compound is made by the chloro- 6- picolines -3- carboxylics oxime acid of 2-.

IR composes (KBr) ν_maxcm^-1：2985,2907,2739,2559,1663,1610,1595,

1561,1541；

H NMR spectroscopy (DMSO-d₆)δppm：2.60 (3H, s), 7.30 (1H, d, J=8.0Hz),

8.14 (1H, d, J=8.0Hz).(d) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -6- picolines simultaneously [3,2-d] isoxazoles

According to embodiment 1 (e) similar the method reaction and processing, by 3- hydroxyl -6- picolines, simultaneously [title compound, yield 71% is made in 3,2-d] isoxazoles and 2- (N- t-butoxycarbonyl aminos) ethanol.

Fusing point：151-152℃；

IR composes (KBr) ν_maxcm^-1：3332,1718,1708,1614,1609,1534；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 2.69 (3H, s),

3.64 (2H, q, J=5.1Hz), 4.51 (2H, t, J=5.1Hz), 4.94 (1H, brs), 7.15 (1H, d, J=8.0Hz),

7.90 (1H, d, J=8.0Hz) (e) 3- (2- amino ethoxies) -6- picolines simultaneously [3,2-d] isoxazole hydrochlorates

According to embodiment 1 (f) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl), simultaneously [title compound, yield 97% is made in 3,2-d] isoxazoles to -6- picolines.

Fusing point：209-213 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3426,3063,3000,2938,1669,1609,1565,

1536,1506；

H NMR spectroscopy (DMSO-d₆)δppm：2.63 (3H, s), 3.30-3.40 (2H, m),

(3H, the brs) of 4.62 (2H, t, J=5.1Hz), 7.40 (1H, d, J=8.0Hz), 8.18 (1H, d, J=8.0Hz), 8.29

The chloro- 4- methyl isophthalic acids of embodiment 733- (2- amino ethoxies) -5-, 2- benzo isoxazole hydrochlorates and the chloro- 7- methyl isophthalic acids of 3- (2- amino ethoxies) -5-, 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 4- methyl isophthalic acids of -5-, 2- benzoisoxazoles and 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 7- methyl isophthalic acids of -5-, 2- benzoisoxazoles

According to embodiment 17 (b) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- chloro- 1,3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 4- methyl isophthalic acids of -5- are made in 2- benzoisoxazoles, 2- benzoisoxazoles, yield is 40%, with 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) the chloro- 7- methyl isophthalic acids of -5-, 2- benzoisoxazoles, yield is 37%.

3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 4- methyl isophthalic acids of -5-, the relevant data of 2- benzoisoxazoles.

Fusing point：140-141℃；

IR composes (KBr) ν_maxcm^-1：3351,1688,1615,1601,1537；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.62 (3H, s),

3.66 (2H, q, J=5.1Hz), 4.50 (2H, t, J=5.1Hz), 4.88 (1H, brs), 7.19 (1H, d, J=8.8Hz),

8.83 (1H, d, J=8.8Hz)

3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) chloro- 7- methyl isophthalic acids of -5-, the relevant data of 2- benzoisoxazoles.

Fusing point：94-95℃；

IR composes (KBr) ν_maxcm^-1：3333,1686,1611,1539；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.48 (3H, s),

3.63 (2H, q, J=5.1Hz), 4.49 (2H, t, J=5.1Hz), 4.94 (1H, brs), 7.29 (1H, d, J=1.8Hz),

The 7 44 chloro- 4- methyl isophthalic acids of (1H, d, J=1.8Hz) (b) 3- (2- amino ethoxies) -5-, 2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) the chloro- 4- methyl isophthalic acids of -5-, the title compound, yield 99% is made in 2- benzoisoxazoles.

Fusing point：223-226 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3451,3009,2970,1645,1618,1605,1536；

H NMR spectroscopy (DMSO-d₆)δppm：2.62 (3H, s), 3.34 (2H, t, J=5.1Hz),

4.63 (2H, t, J=5.1Hz), 7.52 (1H, d, J=8.9Hz), 7.68 (1H, d, J=8.9Hz), the 8.28 chloro- 7- methyl isophthalic acids of (3H, brs) (c) 3- (2- amino ethoxies) -5-, 2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) the chloro- 7- methyl isophthalic acids of -5-, the title compound, yield 98% is made in 2- benzoisoxazoles.

Fusing point：208-211 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3428,3056,2966,2894,2770,1608,1541,

1517；

H NMR spectroscopy (DMSO-d₆)δppm：2.46 (3H, s), 3.34 (2H, t, J=5.1Hz),

(3H, the brs) of 4.60 (2H, t, J=5.1Hz), 7.59 (1H, d, J=1.8Hz), 7.69 (1H, d, J=1.8Hz), 8.32

The bromo- 4- methyl isophthalic acids of embodiment 743- (2- amino ethoxies) -5-, 2- benzo isoxazole hydrochlorates and 3- (2- amino ethoxies) -5- bromine-7-methyls -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) bromo- 4- methyl isophthalic acids of -5-, 2- benzoisoxazoles and 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- bromine-7-methyl -1,2- benzoisoxazoles

According to embodiment 17 (b) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- bromo- 1,3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) bromo- 4- methyl isophthalic acids of -5- are made in 2- benzoisoxazoles, 2- benzoisoxazoles, yield is 7%, with 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- bromine-7-methyl -1,2- benzoisoxazoles, yield is 68%.

3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) bromo- 4- methyl isophthalic acids of -5-, the relevant data of 2- benzoisoxazoles.

Fusing point：140-141℃；

IR composes (KBr) ν_maxcm^-1：3350,1688,1618,1595,1538；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.64 (3H, s),

3.66 (2H, q, J=5.1Hz), 4.50 (2H, t, J=5.1Hz), 4.88 (1H, brs), 7.14 (1H, d, J=8.8Hz),

7.63 (1H, d, J=8.8Hz)

The relevant data of 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- bromine-7-methyl -1,2- benzoisoxazoles.

Fusing point：79-80℃；

IR composes (KBr) ν_maxcm^-1：3350,1692,1612,1535；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.48 (3H, s),

3.65 (2H, q, J=5.1Hz), 4.49 (2H, t, J=5.1Hz), 4.95 (1H, brs), 7.29 (1H, d, J=1.8Hz),

The 7.44 bromo- 4- methyl isophthalic acids of (1H, d, J=1.8Hz) (b) 3- (2- amino ethoxies) -5-, 2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) the bromo- 4- methyl isophthalic acids of -5-, the title compound, yield 96% is made in 2- benzoisoxazoles.

Fusing point：208-212 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3436,3000,1615,1599,1535；

H NMR spectroscopy (DMSO-d₆)δppm：2.64 (3H, s), 3.34 (2H, t, J=5.1Hz),

4.63 (2H, t, J=5.1Hz), 7.46 (1H, d, J=8.9Hz), 7.82 (1H, d, J=8.9Hz), 8.24 (3H, brs) (c) 3- (2- amino ethoxies) -5- bromine-7-methyl -1,2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, the title compound, yield 98% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- bromine-7-methyl -1,2- benzoisoxazoles.

Fusing point：212-215 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3339,3054,2968,2925,2892,1606,1546,

1516；

H NMR spectroscopy (DMSO-d₆)δppm：2.46 (3H, s), 3.33 (2H, t, J=5.1Hz),

(3H, the brs) of 4.60 (2H, t, J=5.1Hz), 7.70 (1H, d, J=1.8Hz), 7.82 (1H, d, J=1.8Hz), 8.28

Embodiment 753- (2- amino ethoxies) -4,5- dimethyl -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4,5- dimethyl -1,2- benzoisoxazoles

According to embodiment 51 (a) similar the method reaction and processing, by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- methyl isophthalic acids, the title compound, yield 73% is made in 2- benzoisoxazoles.

Fusing point：125-126℃；

IR composes (KBr) ν_maxcm^-1：3352,1694,1678,1620,1609,1539；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 2.33 (3H, s), 2.51 (3H, s),

3.65 (2H, q, J=5.1Hz), 4.49 (2H, t, J=5.1Hz), 4.90 (1H, brs), 7.13 (1H, d, J=8.5Hz),

7.29 (1H, d, J=8.5Hz) (b) 3- (2- amino ethoxies) -4,5- dimethyl -1,2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, the title compound, yield 96% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4,5- dimethyl -1,2- benzoisoxazoles.

Fusing point：180-183 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3434,2971,2924,2751,1643,1612,1538；

H NMR spectroscopy (DMSO-d₆)δppm：2.32 (3H, s), 2.51 (3H, s),

3.34 (2H, t, J=5.1Hz), 4.61 (2H, t, J=5.1Hz), 7.31 (1H, d, J=8.5Hz),

7.43 (1H, d, J=8.5Hz), 8.28 (3H, brs)

Embodiment 763- (2- amino ethoxies) -4- methyl -5- methoxyl groups -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- methyl -5- methoxyl group -1,2- benzoisoxazoles

According to embodiment 51 (a) similar the method reaction and processing, the title compound, yield 88% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- methoxyl group -1,2- benzoisoxazoles.

Fusing point：137-138℃；

IR composes (KBr) ν_maxcm^-1：3361,1689,1618,1538；

H NMR spectroscopy (CDCl₃)δppm：1.45 (9H, s), 2.46 (3H, s),

3.65 (2H, q, J=5.1Hz), 3.87 (3H, s), 4.48 (2H, t, J=5.1Hz), 4.90 (1H, brs),

7.12 (1H, d, J=8.9Hz), 7.18 (1H, d, J=8.9Hz).(b) 3- (2- amino ethoxies) -4- methyl -5- methoxyl group -1,2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, the title compound, yield 99% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -4- methyl -5- methoxyl group -1,2- benzoisoxazoles.

Fusing point：173-176 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3423,3008,2971,2920,2842,1617,1601,

1536,1500；

H NMR spectroscopy (DMSO-d₆)δppm：2.44 (3H, s), 3.35 (2H, t, J=5.1Hz),

3.84 (3H, s), 4.60 (2H, t, J=5.1Hz), 7.35 (1H, d, J=9.0Hz), 7.40 (1H, d, J=9.0Hz),

8.32 (3H; brs) embodiments 773- (2- amino ethoxies) -5- carbamoyls -1; 2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- carbamoyl -1,2- benzoisoxazoles

According to embodiment 23 (a) similar the method reaction and processing, the title compound, yield 12% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) bromo- 1,2- benzoisoxazoles of -5-.

Fusing point：178-180℃；

IR composes (KBr) ν_maxcm^-1：3348,3197,1717,1672,1624,1599,1543；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.53 (2H, t, J=5.1Hz), 5.00 (1H, brs), 5.50-6.50 (2H, brs), 7.49 (1H, d, J=8.8Hz),

8.04 (1H, d, J=8.8Hz), 8.16 (1H, s) (b) 3- (2- amino ethoxies) -5- carbamoyl -1,2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, the title compound, yield 96% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- carbamoyl -1,2- benzoisoxazoles.

Fusing point：218-222 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3429,3353,3317,3195,2977,2901,1671,

1622,1596,1546,1501；

H NMR spectroscopy (DMSO-d₆)δppm：3.33 (2H, t, J=5.1Hz),

4.64 (2H, t, J=5.1Hz), 7.51 (1H, s), 7.72 (1H, d, J=8.8Hz), 8.18 (1H, s),

8.21 (1H, d, J=8.8Hz), 8.31 (3H, brs), 8.40 (1H, s)

Embodiment 783- (2- amino ethoxies) -5- cyano group -1,2- benzo isoxazole hydrochlorates (a) 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- cyano group -1,2- benzoisoxazoles

According to embodiment 24 (a) similar the method reaction and processing, the title compound, yield 92% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- carbamoyl -1,2- benzoisoxazoles.

Fusing point：138-140℃；

IR composes (KBr) ν_maxcm^-1：3349,2233,1717,1708,1623,1605,1540,

1527；

H NMR spectroscopy (CDCl₃)δppm：1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.53 (2H, t, J=5.1Hz), 4.93 (1H, brs), 7.56 (1H, d, J=8.8Hz), 7.79 (1H, d, J=8.8Hz),

8.04 (1H, s) (b) 3- (2- amino ethoxies) -5- cyano group -1,2- benzo isoxazole hydrochlorates

According to embodiment 17 (c) similar the method reaction and processing, the title compound, yield 96% are made by 3- (2- (N- t-butoxycarbonyl aminos) ethyoxyl) -5- cyano group -1,2- benzoisoxazoles.

Fusing point：212-216 DEG C (decomposition)；

IR composes (KBr) ν_maxcm^-1：3171,3096,3058,3029,2953,2239,1624,

1601,1544,1518；

7.91 (1H, d；J=8.8Hz), 8.12 (1H, d, J=8.8Hz), 8.35 (3H, brs), 8.43 (1H, s).The monoamine oxidase inhibitory activity of test method 1

According to Biochem.Pharmacol., 12,1439 (1963) and J.Neurochem., 35,109 (1980) methods describeds are measured.In the crude mitochondrial sample that 210 μ l phosphate buffers (pH7.4) and 30 μ l test compounds (being dissolved in the 10%DMSO- aqueous solution) are added to 30 μ l mouse brains (30 μ g proteins), by mixture in preincubate 20 minutes at 38 DEG C.Hereafter, add¹⁴C-2- phenyl ethylamines (PEA, ultimate density：20 μM), to determine B- MAO-B B inhibitory activity；And add¹⁴C-5- hydroxytryptamines (5-HT, ultimate density：100 μM), to determine A- MAO-B B inhibitory activity, by mixture respectively at reaction 20 minutes at 38 DEG C.After the completion of reaction, reactant is set to suspend by adding 2N-HCl (200 μ l), with solvent (ethyl acetate: toluene=1: 1) extraction is produced through the reaction¹⁴The metabolite of C- marks, and use liquid flashing counter measuring¹⁴C radioactivity, to determine to cause described in control group¹⁴Compound concentration (IC during C radioactivities reduction by 50%₅₀).As a result it is as shown in table 17.

The monoamine oxidase inhibitory activity of table 17.

Example No. B- MAO-B B inhibitory activity (IC₅₀)

1^*) 0.37nM

2 1.85nM

5^*) 1.35nM

6^*) 5.60nM

7^*) 0.56nM

8^*) 0.56nM

9 20.0nM

10(e) 10.2nM

10(f) 13.5nM

11 2.8nM

12 26.5nM

13 27.5nM

14 21.5nM

15^*) 0.32nM

17 4.2nM

21 4.7nM

24 6.8nM

26 2.7nM

33 4.5nM

34 2.2nM

35 9.0nM

38 2.95nM

42 18.0nM

44 6.0nM

56 6.6nM

Compound A^**) 2.35μM

Compound B^***)4.70 μM note：^*) to show B- MAO-B B inhibitory activity be 4500-55000 times of A- MAO-B B inhibitory activity.^**) 3- (2-N- methylaminos) ethyoxyl -1,2- benzoisoxazole.^***) 3- (2-N, N '-dimethylamino) ethyoxyl -1,2- benzoisoxazole.The hard capsule of example of formulations 1

The capsule of single dose is made by loading powdered compounds, 150mg lactose, 50mg celluloses and 6mg magnesium stearates described in 100mg embodiments 1 into each standard hard gelatin capsule, prepared single dosage capsule agent is washed and dried, hard capsule is obtained.

[industrial applicibility]

Isoxazole derivatives (I) of the present invention and (II) have significant B- MAO-B Bs inhibitory activity and A- MAO-B Bs inhibitory activity (particularly having high inhibition effect to B- MAO-B Bs) and the toxicity with the bottom of compared with, therefore they can be used as the therapeutic agent or prophylactic of neuropathies such as Parkinson's, depression, alzheimer's disease etc. (particularly Parkinson's).

When compound of the present invention (I) and (II) or its pharmaceutically acceptable salt are used as above-mentioned neuropathic therapeutic agent or prophylactic, the compound can be mixed with the form oral medication such as tablet, capsule, granule, pulvis, syrup with itself or with suitable pharmaceutically acceptable excipient, diluent etc., or through injection or suppository non-oral administration.

These preparation useful additives are made through conventional method, the additive such as excipient (such as sugar derivatives such as lactose, sucrose, fructose, mannitol and D-sorbite；Starch derivatives such as cornstarch, horse bell administration starch, alphalise starch, dextrin and CMS；Cellulose derivative such as microcrystalline cellulose, low substituted hydroxypropyl cellulose, HPMC, Carmellose, carboxylic cellulose formiate calcium and internally crosslinked carmellose sodium；Arabic gum；Glucan；Amylopectin (pullulan)；Silicate derivative such as light anhydrous silicic acid, synthetic aluminium silicate and Magnesiumaluminumsilicate；Phosphate such as calcium phosphate；Carbonate such as calcium carbonate；Sulfate is such as calcium sulfate), adhesive (such as above-mentioned excipient；Gelatin；Polyvinylpyrrolidone；Polyethylene glycol etc.), decay agent (such as above-mentioned excipient；The carmellose sodium of crosslinking, sodium carboxymethyl starch, the starch through chemical modification are such as the polyvinylpyrrolidone of crosslinking, cellulose derivative), lubricant (such as talcum；Stearic acid；Metallic stearates such as calcium stearate and magnesium stearate；Silica gel；Shellac such as propolis and spermaceti；Boric acid；Ethylene glycol；Carboxylic acid such as fumaric acid and adipic acid；Carboxylic acid sodium such as sodium benzoate；Sulfate such as sodium sulphate；Leucine；Lauryl sulfate such as lauryl sodium sulfate, Stepanol MG；Silicic acid such as silicic acid anhydride and hydrate of silicic acid；Starch derivatives described in above-mentioned excipient), insecticide (such as p-hydroxybenzoate such as methylparoban and nipasol；Alcohol such as methaform, phenmethylol and benzoglycols；Benzalkonium chloride；Phenols such as phenol and cresols；Thiomersalate；Acetic anhydride；Sorbic acid etc.), flavor enhancement or flavoring agent (such as usually used sweetener, acid, flavouring agent), diluent and solvent for injection (such as water, ethanol and glycerine).Dosage used can be different according to symptom, age etc.,, but it is preferred that, in the case of oral, the minimum flow that adult applies every time daily is 1mg (preferably 10mg) and maximum amount is 2000mg (preferably 400mg), in the case of intravenous administration, each minimum flow is 0.1mg (preferably 1mg) daily and maximum amount is 500mg (preferably 300mg), and according to the difference of symptom, daily can medication 1-6 times.

Claims

1. following formula (I) compound or its pharmaceutically acceptable salt,

Wherein R¹Represent hydrogen atom；Halogen atom；Alkyl with 1~6 carbon atom；By halogen-or by the alkoxy with 1~4 carbon atom-alkyl substituted and that there is 1~4 carbon atom；Alkoxy with 1~6 carbon atom；Halogenated alkoxy with 1~6 carbon atom；Hydroxyl；Alkylthio group with 1~6 carbon atom；Amino；Wherein moieties have the alkyl monosubstituted amino of 1~6 carbon atom；Each of which moieties independently have the dialkyl amido of 1~6 carbon atom；Alkanoyl with 1~6 carbon atom；Alkanoyl amido with 1~6 carbon atom；Alkanoyloxy with 1~6 carbon atom；Alkoxy carbonyl group with 1~6 carbon atom；Carboxyl；Wherein alkylthio moieties have the alkylthiothiocarbonyl of 1~6 carbon atom；Carbamoyl；Wherein moieties have the alkyl monosubstituted amino formoxyl of 1~6 carbon atom；Each of which moieties independently have the dialkyl carbamoyl of 1~6 carbon atom；Nitro or cyano group, R²Represent amino group, m represents 1-3 integer, n represents 1-6 integer, ring A represent the phenyl ring Yu isoxazole rings fusion of Yu isoxazole rings fusion naphthalene nucleus or the fusion of Yu isoxazole rings containing 1 or 2 heteroatomic 5- or 6- members heteroaromatic for being selected from oxygen atom, nitrogen-atoms and sulphur atom, and X represents oxygen atom or sulphur atom, and condition is, when m is 2 or 3 integer, each substituent R¹It is identical or different.

2. compound according to claim 1 or its pharmaceutically acceptable salt, wherein R¹Represent hydrogen atom, halogen atom, alkyl with 1~4 carbon atom, methyl fluoride, difluoromethyl, trifluoromethyl, 2- fluoro ethyls, 2- chloroethyls, 2,2,2- trifluoroethyls, methoxy, methoxy ethyl, alkoxy with 1~4 carbon atom, fluorine methoxyl group, chloromethane epoxide, difluoro-methoxy, dichloro methoxyl group, trifluoromethoxy, trichloromethoxy, 1- fluorine ethyoxyls, 2- fluorine ethyoxyls, 2- chloroethoxies, 2,2,2- trifluoro ethoxies, hydroxyl, alkylthio group with 1~4 carbon atom, amino, wherein moieties have the alkyl monosubstituted amino of 1~4 carbon atom, each of which moieties independently have the dialkyl amido of 1~4 carbon atom, formoxyl, acetyl group, formamido group, acetylamino, alkanoyloxy with 1~4 carbon atom, alkoxy carbonyl group with 1~4 carbon atom, carboxyl, methyl mercapto thiocarbonyl, ethylmercapto group thiocarbonyl, carbamoyl, methylcarbamoyl, ethylaminocarbonyl, formyl-dimethylamino, diethylamino formoxyl, nitro or cyano group.

3. compound according to claim 1 or its pharmaceutically acceptable salt, wherein R¹Represent hydrogen atom, halogen atom, alkyl with 1~4 carbon atom, methyl fluoride, difluoromethyl, trifluoromethyl, 2- fluoro ethyls, 2, 2, 2- trifluoroethyls, methoxy, methoxy ethyl, alkoxy with 1~4 carbon atom, difluoro-methoxy, hydroxyl, alkylthio group with 1~4 carbon atom, amino, methylamino, ethylamino, dimethylamino, lignocaine, formoxyl, acetyl group, formamido group, acetylamino, alkoxy carbonyl group with 1~4 carbon atom, carboxyl, carbamoyl, methylcarbamoyl, ethylaminocarbonyl, formyl-dimethylamino, diethylamino formoxyl, nitro or cyano group.

4. compound according to claim 1 or its pharmaceutically acceptable salt, wherein R¹Represent hydrogen atom, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, trifluoromethyl, methoxyl group, ethyoxyl, difluoro-methoxy, hydroxyl, methyl mercapto, ethylmercapto group, amino, methylamino, ethylamino, dimethylamino, formyloxy, acetoxyl group, methoxycarbonyl group, carbethoxyl group, carboxyl, carbamoyl, nitro or cyano group.

5. compound according to claim 1 or its pharmaceutically acceptable salt, wherein R¹Represent hydrogen atom, fluorine atom, chlorine atom, bromine atoms, methyl, methoxyl group, methyl mercapto, difluoro-methoxy, methoxycarbonyl group, nitro or cyano group.

6. according to the compound of any claim in claim 1-5 or its pharmaceutically acceptable salt, wherein m is 2.

7. according to the compound of any claim in claim 1-5 or its pharmaceutically acceptable salt, wherein m is 1.

8. according to the compound of any claim in claim 1-5 or its pharmaceutically acceptable salt, wherein n is 2-4.

9. according to the compound of any claim in claim 1-5 or its pharmaceutically acceptable salt, wherein n is 2.

10. according to the compound of any claim in claim 1-5 or its pharmaceutically acceptable salt, its middle ring A is phenyl, naphthyl, furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridine radicals, pyrazinyl, pyrimidine radicals or pyridazine basic ring.

11. according to the compound of any claim in claim 1-5 or its pharmaceutically acceptable salt, its middle ring A is phenyl, naphthyl or pyridyl ring.

12. according to the compound of any claim in claim 1-5 or its pharmaceutically acceptable salt, its middle ring A is phenyl or pyridyl ring.

13. according to the compound of any claim in claim 1-5 or its pharmaceutically acceptable salt, its middle ring A is benzyl ring.

14. according to the compound of any claim in claim 1-5 or its pharmaceutically acceptable salt, wherein X is oxygen atom.

15. compound according to claim 1 or its pharmaceutically acceptable salt, the compound are selected from

3- (2- amino ethoxies) benzoisoxazole,

3- (2- aminoethanethios) benzoisoxazole,

3- (2- amino ethoxies)-fluorine benzoisoxazole,

3- (2- aminoethanethios)-fluorine benzoisoxazole,

3- (2- amino ethoxies)-fluoro-2-methyl benzoisoxazole,

3- (2- aminoethanethios)-fluoro-2-methyl benzoisoxazole,

3- (2- amino ethoxies)-fluoro- methyl mercapto benzoisoxazole,

3- (2- amino ethoxies)-fluoro- methoxycarbonyl group benzo isoxazole,

3- (2- amino ethoxies)-fluoro- carbamoyl benzoisoxazole,

3- (2- amino ethoxies)-fluoro- cyano group benzoisoxazole,

3- (2- aminoethanethios)-fluoro- cyano group benzoisoxazole,

3- (2- amino ethoxies)-Lv benzoisoxazoles,

3- (2- aminoethanethios)-Lv benzoisoxazoles,

3- (2- amino ethoxies)-dichloro benzoisoxazole,

3- (2- aminoethanethios)-dichloro benzoisoxazole,

3- (2- amino ethoxies)-chloro- methyl benzoisoxazole,

3- (2- aminoethanethios)-chloro- methyl benzoisoxazole,

3- (2- amino ethoxies)-chloro- carbamoyl benzoisoxazole,

3- (2- amino ethoxies)-chloro- cyano group benzoisoxazole,

3- (2- aminoethanethios)-chloro- cyano group benzoisoxazole,

3- (2- amino ethoxies)-dichloro-methyl benzoisoxazole,

3- (2- amino ethoxies)-bromine benzoisoxazole,

3- (2- amino ethoxies)-bromo- methyl benzoisoxazole,

3- (2- amino ethoxies)-methyl benzoisoxazole,

3- (2- aminoethanethios)-methyl benzoisoxazole,

3- (2- amino ethoxies)-dimethylbiphenyl isoxazole,

3- (2- amino ethoxies)-methyl-methoxyl group benzoisoxazole,

3- (2- amino ethoxies)-methyl-methylthio benzoisoxazole,

3- (2- amino ethoxies)-methyl-methoxycarbonyl group benzo isoxazole,

3- (2- amino ethoxies)-methyl-cabanaoyl benzoisoxazole,

3- (2- amino ethoxies)-methyl-cyano group benzoisoxazole,

3- (2- amino ethoxies)-trifluoromethyl benzo isoxazole,

3- (2- amino ethoxies)-methoxyl group benzoisoxazole,

3- (2- aminoethanethios)-methoxyl group benzoisoxazole,

3- (2- amino ethoxies)-difluoro-methoxy benzo isoxazole,

3- (2- amino ethoxies)-hydroxy benzo isoxazole,

3- (2- amino ethoxies)-amino benzoisoxazole,

3- (2- aminoethanethios)-amino benzoisoxazole,

3- (2- amino ethoxies)-methylamino benzoisoxazole,

3- (2- amino ethoxies)-dimethylamino benzo isoxazole,

3- (2- amino ethoxies)-acetoxyl group benzo isoxazole,

3- (2- amino ethoxies)-carboxyl benzoisoxazole,

3- (2- amino ethoxies)-methoxycarbonyl group benzo isoxazole,

3- (2- amino ethoxies)-carbamoyl benzoisoxazole,

3- (2- amino ethoxies)-nitro benzoisoxazole,

3- (2- aminoethanethios)-nitro benzoisoxazole,

3- (2- amino ethoxies)-cyano group benzoisoxazole,

3- (2- amino ethoxies)-naphthalene Bing isoxazoles,

3- (2- amino ethoxies)-pyrido isoxazole,

3- (2- amino ethoxies)-chloropyridine Bing isoxazoles,

3- (2- aminoethanethios)-chloropyridine Bing isoxazoles,

3- (2- amino ethoxies)-picoline Bing isoxazoles, and

3- (2- amino ethoxies)-trifluoromethyl pyridine Bing isoxazoles.

16. compound according to claim 1 and its pharmaceutically acceptable salt, the compound are selected from：

3- (2- amino ethoxies) -1,2- benzoisoxazoles,

Fluoro- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -5-,

The fluoro- 4- methyl isophthalic acids of 3- (2- amino ethoxies) -5-, 2- benzoisoxazoles,

Fluoro- 1, the 2- benzoisoxazoles of 3- (2- aminoethanethios) -5-,

Chloro- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -5-,

Chloro- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -5,7- bis-,

The chloro- 7- methyl isophthalic acids of 3- (2- aminoethanethios) -5-, 2- benzoisoxazoles,

Chloro- 1, the 2- benzoisoxazoles of 3- (2- aminoethanethios) -5-,

Chloro- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -6-,

Chloro- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -7-,

Bromo- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -5-,

3- (2- amino ethoxies) -5- methyl isophthalic acids, 2- benzoisoxazoles,

3- (2- aminoethanethios) -5- methyl isophthalic acids, 2- benzoisoxazoles,

3- (2- amino ethoxies) -6- methyl isophthalic acids, 2- benzoisoxazoles,

3- (2- amino ethoxies) -7- methyl isophthalic acids, 2- benzoisoxazoles,

3- (2- amino ethoxies) -5- methoxyl group -1,2- benzoisoxazoles,

3- (2- aminoethanethios) -5- methoxyl group -1,2- benzoisoxazoles,

3- (2- amino ethoxies) -5- difluoro-methoxy -1,2- benzoisoxazoles,

Fluoro- 4- methyl mercaptos -1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -5-,

3- (2- amino ethoxies) -5- methoxycarbonyl group -1,2- benzoisoxazoles,

3- (2- amino ethoxies) -5- nitro -1,2- benzoisoxazoles,

3- (2- aminoethanethios) -5- nitro -1,2- benzoisoxazoles,

3- (2- amino ethoxies) -4- cyano group -1,2- benzoisoxazoles, and

3- (2- amino ethoxies) pyrido [3,2-d] isoxazoles.

17. compound according to claim 1 and its pharmaceutically acceptable salt, the compound are selected from：

3- (2- amino ethoxies) -4,7- dimethyl -1,2- benzoisoxazoles,

The fluoro- 7- methyl isophthalic acids of 3- (2- amino ethoxies) -4-, 2- benzoisoxazoles, and

3- (2- amino ethoxies) -4- trifluoromethyl pyridines simultaneously [3,2-d] isoxazoles.

18. compound according to claim 1 and its pharmaceutically acceptable salt, the compound are fluoro- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -4- cyano group -5-.

19. compound according to claim 1 and its pharmaceutically acceptable salt, the compound are the fluoro- 4- methyl isophthalic acids of 3- (2- amino ethoxies) -5-, 2- benzoisoxazoles.

20. a kind of pharmaceutical composition, wherein formula (I) compound or its pharmaceutically acceptable salt and the pharmaceutical carrier or diluent being mixed with any one of the claim 1-19 containing effective dose.

(21. I) isoxazole derivativeses or its pharmaceutically acceptable salt are preparing the application in treating and preventing neuropathic medicine at least one formula any one of claim 1-19.

22. application according to claim 21, wherein described neuropathy is selected from Parkinson's, depression and alzheimer's disease.

23. according to the application of claim 21 or 22, wherein the compound is fluoro- 1, the 2- benzoisoxazoles of 3- (2- amino ethoxies) -4- cyano group -5-.

24. according to the application of claim 21 or 22, wherein the compound is the fluoro- 4- methyl isophthalic acids of 3- (2- amino ethoxies) -5-, 2- benzoisoxazoles.

25. the method for formula (I) compound or its pharmaceutically acceptable salt described in preparation claim 1, methods described includes：(1) general formula (XV) compound and halogenating agent are reacted, obtain the isoxazole derivatives of halo-of general formula (XVI),

Wherein R¹Represent hydrogen atom；Halogen atom；Alkyl with 1~6 carbon atom；By halogen-or the alkoxy with 1~4 carbon atom-substituted and with the alkyl of 1~4 carbon atom；Alkoxy with 1~6 carbon atom；Halogenated alkoxy with 1~6 carbon atom；Hydroxyl；Alkylthio group with 1~6 carbon atom；Amino；Wherein moieties have the alkyl monosubstituted amino of 1~6 carbon atom；Each of which moieties independently have the dialkyl amido of 1~6 carbon atom；Alkanoyl with 1~6 carbon atom；Alkanoyl amido with 1~6 carbon atom；Alkanoyloxy with 1~6 carbon atom；Alkoxy carbonyl group with 1~6 carbon atom；Carboxyl；Wherein alkylthio moieties have (alkylthio group) thiocarbonyl of 1~6 carbon atom；Carbamoyl；Wherein moieties have the alkyl monosubstituted amino formoxyl of 1~6 carbon atom；Each of which moieties independently have the dialkyl carbamoyl of 1~6 carbon atom；Nitro or cyano group,

M represents 1-3 integer,

A represent Yu isoxazole rings fusion phenyl ring, Yu isoxazole ring condense naphthalene nucleus or Yu isoxazole rings fusion containing 1 or 2 be selected from oxygen atom, nitrogen-atoms and sulphur atom heteroatomic 5- or 6- members heteroaromatic,

Wherein R¹, m and A as described above, Z represents halogen atom, then the compound (XVI) and general formula (XVII) compound are reacted, obtain general formula (XVIII) isoxazole derivativeses,

HX-(CH₂)_n-R⁴

(XVII)

Wherein R⁴Protected amino is represented, n represents 1-6 integer, and X represents oxygen atom or sulphur atom；

Wherein R¹、R⁴, m, n, A and X it is as described above, or (2) are in the presence of phosphine-derivatives and azo-compound, compound (XV) and general formula (XVIIa ') compound are reacted, general formula (XVIIIa) isoxazole derivativeses are obtained

HO-(CH₂)_n-R⁴

(XVIIa′)

Wherein R⁴As described above；

Wherein R¹、R⁴, m, n, A and X it is as described above, or (3) are in atent solvent, in the presence of a base, compound (XV) and general formula (XVIIa ") compound are reacted; obtain general formula (XVIIIa) isoxazole derivativeses

Ya-(CH₂)_n-R⁴

(XVIIa″)

Wherein R⁴With n as described above, and Ya be leaving group,

Wherein R¹、R⁴, m, n, A and X it is as described above；Or (4) remove amino protecting group in above-mentioned steps (1), (2) or (3) in obtained formula (XVIII) or (XVIIIa), and formula (I) compound as claimed in claim 1 is made.

26. method according to claim 25,

Wherein R¹Represent hydrogen atom, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, trifluoromethyl, methoxyl group, ethyoxyl, difluoro-methoxy, hydroxyl, methyl mercapto, ethylmercapto group, amino, methylamino, ethylamino, dimethylamino, formyloxy, acetoxyl group, methoxycarbonyl group, carbethoxyl group, carboxyl, carbamoyl, nitro or cyano group

N is 2, and

Ring A represents phenyl, naphthyl or pyridyl ring.

27. method according to claim 25, wherein R¹Hydrogen atom, fluorine atom, chlorine atom, bromine atoms, methyl, methoxyl group, methyl mercapto, difluoro-methoxy, methoxycarbonyl group, nitro or cyano group are represented,

R⁴Represent t-butoxycarbonyl amino,

M is 2,

N is 2,

Ring A represents phenyl or pyridyl ring,

X represents oxygen atom, and

Z represents fluorine atom or chlorine atom.

28. the compound of formula (XVIII),

Wherein, R¹, m, n, A and X as defined in claim 1, R⁴It is the amino for being selected from following radical protection：

C₁-C₆Alkanoyl；

By halogen or C₁-C₄The C of alkoxy substitution₁-C₄Alkanoyl；

Undersaturated C₁-C₄Alkanoyl；

Can be by halogen, C₁-C₄Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkoxy carbonyl group, C₆-C₁₀Aryl or the C of nitro substitution₆-C₁₀Aryl carbonyl；

Can be by halogen or three C₁-C₄The C of aIkylsilyl groups substitution₁-C₄Alkoxy carbonyl group；

C₂-C₅Chain ene keto carbonyl；

Aryl dicarbapentaborane group；

Aromatic alkyl group；With

The C that can be replaced by methoxyl group or nitro₇-C₁₅Aromatic alkoxy carbonyl group.

29. the compound of formula (XVIII) according to claim 28, wherein, R⁴It is the amino for being selected from following radical protection：C₁-C₄Alkanoyl, trifluoroacetyl group, Methoxyacetyl, benzoyl, α-naphthoyl, β-naphthoyl, 4- methoxybenzoyls base, 4- nitro benzoyls, methoxycarbonyl group, carbethoxyl group, tertbutyloxycarbonyl, 2; 2,2- trichloro-ethoxycarbonyls, triethylsilyl methoxycarbonyl group, 2- trimethyl silyls carbethoxyl group, vinyloxycarbonyl, allyloxycarbonyl, phthalyl, benzyl, benzyloxycarbonyl group and nitrobenzyloxycarbonyl group.

30. the compound of formula (XVIII) according to claim 29, wherein, R⁴It is the amino for being selected from following radical protection：Formoxyl, acetyl group, benzoyl, 4- methoxybenzoyls base, 4- nitro benzoyls, methoxycarbonyl group, carbethoxyl group, tertbutyloxycarbonyl, phthalyl, benzyl, benzyloxycarbonyl group and to nitrobenzyloxycarbonyl group.